Composition

ABSTRACT

Pharmaceutical compositions and methods for the treatment of neoplastic disease and comprising the combination of a taxane, such as docetaxel, with a CYP3A4 inhibitor, such as ritonavir. Methods of treatment of neoplastic disease incorporating the administration of a taxane and the administration of a CYP3A4 inhibitor, either simultaneously or separately, are also included. Further, kits for carrying out the methods are included. Solid pharmaceutical taxane compositions for oral administration comprising a substantially amorphous taxane, a carrier and a surfactant are also included.

The invention relates to pharmaceutical compositions. In particular,though not exclusively, it relates to compositions and methods for thetreatment of neoplastic disease.

The administration of drugs in oral form provides a number ofadvantages. The availability of an oral anticancer drug is importantwhen treatment must be applied chronically to be optimally effectivee.g., the 5-fluorouracil (5-FU) prodrugs (e.g. capecitabine) and drugsthat interfere with signal transduction pathways or with theangiogenesis process [1]. In addition, oral drugs can be administered onan outpatient basis or at home, increasing convenience and patientquality of life, and possibly decreasing the costs by reducing hospitaladmissions [2]. Therefore, it is advantageous to try to administeranticancer drugs orally.

In general, the oral administration of drugs is convenient andpractical. However, the majority of anticancer drugs unfortunately havea low and variable oral bioavailability [1]. Typical examples are thewidely used taxanes, docetaxel and paclitaxel, which have an oralbioavailability of less than 10% [3, 4]. Several other anticancer agentswith higher bioavailability demonstrate higher variability. Examplesinclude the topoisomerase I inhibitors, the vinca alkaloids, andmitoxantrone [1, 5, 6]. In view of the narrow therapeutic window, thevariable bioavailability may result in unanticipated toxicity ordecreased efficacy when therapeutic plasma levels are not achieved.Hellriegel et al. demonstrated in a study that the plasma levels afteroral administration are generally more variable than after i.v.administration [7]. Adequate oral bioavailability is important when theperiod of drug exposure is a major determinant of anticancer therapy[8]. Adequate oral bioavailability is also important to prevent highlocal drug concentrations in the gastro-intestinal tract that may givelocal toxicity.

Chen et al. [95] conducted experiments to try to improve the solubilityof the anticancer drug docetaxel in order to improve itsbioavailability. Chen et al. tried using solid dispersions of docetaxelwith various carriers, namely glyceryl monosterate, PVP-K30 or poloxamer188. Chen et al. found that poloxamer 188 increased the solubility ofdocetaxel to about 3.3 μg/ml after 20 minutes (in a standard dissolutiontest) and to a maximum of about 5.5 μg/ml after about 120 minutes when adocetaxel to poloxamer ratio of 5:95 was used. PVP-K30 only increasedthe solubility of docetaxel to about 0.8 μg/ml after 20 minutes and to amaximum of about 4.2 μg/ml after about 300 minutes. Glycerolmonostearate hardly increased the solubility of docetaxel at all. Thus,the solubility and dissolution rate of docetaxel was not increased to aparticularly high level.

There are a number of important mechanisms that can explain the variableand/or low oral bioavailability of anticancer drugs, such as highaffinity for drug transporters in the gastrointestinal tract, whichlimits absorption, and high extraction of the drug by extensivemetabolism in the intestine and/or liver (first-pass effect) [1, 4, 9].Other important factors include structural instability and limitedsolubility of the drug in the gastrointestinal fluids, drug-drug anddrug-food interactions, motility disorders, obstructive disorders,existence of nausea and vomiting or local toxicity in thegastro-intestinal tract.

With regard to the drug transporters and metabolic enzymes that affectthe bioavailability of oral drugs, it has been speculated that the maindrug transporter and metabolic enzymes responsible for the low/variableoral bioavailability of anticancer drugs are P-glycoprotein (P-gp) andcytochrome P450 (CYP) isoenzymes.

P-glycoprotein (P-gp) is a membrane-bound multidrug transporter whichfunctions as an energy-dependent transport or efflux pump to decreaseintracellular accumulation of drugs by exporting xenobiotics from thecell. P-gp has been identified in normal tissues with an excretoryfunction such as the biliary canalicular membrane of hepatocytes, theluminal membrane of endothelial cells in the blood-brain barrier andblood-testis barrier, the apical membrane of the syncytial trophoblastsof the placenta, the epithelial apical membrane of the intestine, andthe renal proximal tubules. P-gp may possess an important barrierfunction in protecting tissues against xenotoxins [9-12].

It is believed that P-gp prevents certain pharmaceutical compounds fromtransversing the mucosal cells of the small intestine and, therefore,from being absorbed into the systemic circulation. A wide range of drugswith varying physicochemical characteristics and pharmacologicalactivity, such as verapamil, quinidine, and cyclosporin A (CsA) and thenew active blockers GF120918 (elacridar), LY335979 (zosuquidar), andR101933 have been shown in clinical studies to modulate P-gp [13-18].Mechanisms by which P-gp modulators can influence the pharmacokineticsof the anticancer drug after i.v. administration are competition forcytochrome P450 (CYP)-mediated intestinal or liver metabolism,inhibition of P-gp-mediated biliary excretion, intestinal transport, andinhibition of renal elimination [19, 20]. Only a few prospectiverandomized studies combining an anticancer agent with or without amodulator have been performed. These studies revealed that dosereductions of the anticancer drug, when combined with a modulator, werenecessary to prevent severe drug-related toxicity. In addition, thesestudies did not show any survival benefit for the combination of ananticancer drug with a modulator [21-23].

For many anticancer drugs, cytochrome P450 (CYP) is the main oxidativedrug metabolizing enzyme system. CYP isoenzymes are highly expressed inthe liver and intestines, but the exact contribution of each isoenzymein the metabolism of drugs is unknown. It is recognised that intestinalextraction by this enzyme system plays an important role in limitingoral bioavailability of drugs [31]. Humans have four identifiedfunctional CYP3A enzymes which are the predominant drug metabolizingenzymes and account for approximately 30% of hepatic CYP and more than70% of intestinal CYP expression [24, 30, 32, 33].

Some P-gp modulators also appear to be substrates for CYP3A, anisoenzyme of the CYP system. The overlap in substrate selectivity forP-gp and CYP3A, combined with their tissue localization, suggests thatthese two proteins cooperate and constitute an absorption barrieragainst toxic xenobiotics [24-26]. Cummins et al. have confirmed thisand showed that P-gp can affect intestinal drug metabolism (especiallythe isoenzyme CYP3A4) by controlling the access of a drug to theintracellular metabolizing enzyme system [27]. Therefore, it appearsthat CYP3A and P-gp may play a role in limited and/or variable oralbioavailability of shared substrate drugs in the intestines.

The taxanes, paclitaxel and docetaxel, have proven anticancer activityin several tumour types (e.g., breast, ovarian, head and neck cancer,and non-small cell lung cancer [NSCLC]). Currently, the drugs areadministered intravenously at different dosages and schedules [34].However, in oral formulations, the taxanes have very lowbioavailability. This is speculated to be due to the action of P-gp andCYP3A. Studies attempting to increase the bioavailability of orallyadministered drugs have been performed in mice and humans with severalanticancer drugs (e.g., the taxanes).

When paclitaxel is administered orally, the bioavailability is very low(<10%). This is caused by the high affinity of paclitaxel for P-gp,which is present in the gastrointestinal tract [4, 10, 35, 36]. Inaddition, presystemic elimination in the intestinal wall and liver bythe CYP isoenzymes 3A4 and 2C8 may also play a role in the low oralbioavailability of paclitaxel [37-39]. Recent studies with wild-typemice and mdr1a P-gp knockout mice have shown unambiguously that P-gplimits the absorption of paclitaxel. In a proof-of-concept study inknockout mice compared with wild-type mice, the investigatorsdemonstrated a sixfold and a twofold increase of the area under theplasma concentration-time curve (AUC) of paclitaxel after oral and i.v.administration, respectively [4]. The fraction of unchanged paclitaxelrecovered from the faeces of wild-type mice after oral administrationwas 87% of the dose compared with 3% in mdr1a P-gp knockout mice.Despite the complete absorption from the gastrointestinal tract, thebioavailability did not increase to 100%, probably due to first-passintestinal/hepatic extraction [4, 40].

Based on this observation, several new studies have been initiated withP-gp inhibitors in combination with paclitaxel in order to enhance theoral bioavailability. Studies in mice revealed that coadministration ofSDZ PSC833, a cyclosporin D analogue and potent P-gp inhibitor, withpaclitaxel resulted in a 10-fold increase in systemic exposure [41]. Asimilar study was performed with CsA and paclitaxel that has showncomparable effects [42]. The oral bioavailability in wild-type miceincreased from 9% to 67% when CsA was coadministered. It was also notedthat the plasma levels of paclitaxel obtained in wild-type micecotreated with CsA were even higher than those obtained in knockout micethat were treated with oral paclitaxel without CsA. This can beexplained by increased uptake by inhibition of P-gp in thegastrointestinal tract and decreased elimination by inhibition of CYP3A[42-45]. However, blockade of other yet unidentified drug transportersor drug eliminating pathways cannot be ruled out.

The use of CsA for long-term oral dosing has been associated withimmunosuppressive effects which are detrimental to the health of thesubject. Therefore, an alternative, non-immunosuppressive P-gp blocker,GF120918, was explored to enhance the oral bioavailability ofpaclitaxel. GF120918 was primarily developed to reverse P-gp-mediatedmulti-drug resistance in tumours [16]. In a recently published study,Bardelmeijer et al. demonstrated that GF120918 significantly increasedthe oral bioavailability of paclitaxel [46]. The oral bioavailability ofpaclitaxel in wild-type mice increased from 8.5% to 40% and thepharmacokinetics of paclitaxel in wild type mice receiving GF120918 weresimilar to that found in mdr1a/b P-gp knockout mice. Thus, GF120918effectively blocks P-gp in the intestines and most likely does notinterfere with other pathways involved in paclitaxel uptake orelimination. Of note, it was recently demonstrated that GF120918 is alsoan effective inhibitor of the ABC drug transporter BCRP (ABCG2) [28,29].

Docetaxel is also a substrate of P-gp, first shown in 1994 by Wils etal. [47, 48]. Because of the encouraging results obtained withpaclitaxel in combination with P-gp inhibitors, studies in mice werealso performed with docetaxel. These studies confirmed that P-gp alsoplays an important role in the low bioavailability of docetaxel. The AUCof oral docetaxel increased ninefold by coadministration with CsA [49].In addition, coadministration of ritonavir, an inhibitor of CYP3A4 withminor P-gp inhibiting properties, was tested in mice. CYP3A4 is themajor enzyme responsible for metabolic breakdown of docetaxel in humans[50]. The inventors executed preclinical studies in mice in whichritonavir was coadministered with docetaxel and showed an increase inthe apparent bioavailability from 4% to 183%. Extensive first-passmetabolism might also largely contribute to the low bioavailability oforal docetaxel in mice [49]. Cytochrome P450 enzymes in the intestinesof mice (referred to as Cyp) are different from those found in humansand have different substrate specificities. Further, regulation ofexpression of CYPs between mice and humans differs considerably due todifferences in the activity, expression and regulation of transcriptionfactors, for example, PXR for human CYP3A [88-92]. Therefore, thesestudies in mice cannot be relied upon to give any indication of theresults in humans since the physiology, enzymes, etc. of mice arecompletely different to humans. Accordingly, mouse data cannot simply beextrapolated to humans. Further, this study in mice used an extremelyhigh dose of docetaxel (10-30 mg/kg) which would be lethal in humansubjects, and also a high dose of ritonavir (12.5 mg/kg). For a 72 kgindividual this would mean 720-2160 mg of docetaxel. Patients are,however, now usually treated in the clinic with docetaxel dosagesbetween 100 and 200 mg (intravenously). Clearly, due to the high levelof drugs that were administered, this approach is not possible inhumans. In addition, the mouse data do not provide any evidence aboutthe safety of the oral approach with this combination in humans.

Based on the extensive preclinical results in mice, several clinicalproof-of-concept studies were initiated. Patients with solid tumoursreceived one course of 60 mg/m² oral paclitaxel as a single agent, or 60mg/m² oral paclitaxel in combination with 15 mg/kg CsA. Coadministrationof oral CsA resulted in an eightfold increase in the systemic exposureto oral paclitaxel, and the apparent bioavailability of oral paclitaxelin this study rose from 4% without CsA to 47% with CsA [3]. Thisincrease in systemic exposure was most likely caused by inhibition ofP-gp in the gastrointestinal tract, but inhibition of paclitaxelmetabolism also may have contributed to the effect, as was concludedfrom the preclinical studies [41, 42]. In order to further increase thesystemic exposure of paclitaxel, a dose escalation study with oralpaclitaxel in combination with CsA revealed that the maximum tolerateddose was 300 mg/m² and the increase in AUC at the higher doses was notproportional with dose [52]. At this highest dose level, a mass balancestudy was performed to measure faecal excretion. At the highest doselevel of 300 mg/m², the total faecal excretion was 76%, 61% of which wasthe parent drug, which can be explained by incomplete absorption oforally administered paclitaxel from the gastrointestinal tract [53]. Itwas speculated that the high amount of the cosolvent Cremophor EL in thepaclitaxel i.v. formulations used for oral administration preventedcomplete absorption of orally applied paclitaxel. In addition, CremophorEL, which is responsible for the nonlinear pharmacokinetics of i.v.paclitaxel and for the severe hypersensitivity reactions, was notabsorbed following oral administration of paclitaxel, as plasma levelsof Cremophor EL were not detected [54-56]. This may be an additionaladvantage of oral paclitaxel administration [51, 52]. Subsequently, inorder to increase the duration of systemic exposure of oral paclitaxelabove a threshold level of 0.1 μM, a twice daily (b.i.d.) dose regimenof oral paclitaxel in combination with CsA was explored in patients. Atthe dose level of 2×90 mg/m², adequately long systemic exposure ofpaclitaxel above the level of 0.1 μM was reached with a good safetyprofile [57]. In these studies the patients ingested orally theintravenous paclitaxel formulation (also containing Cremophor EL andethanol) [57]. Additionally, a dose-finding study of oral paclitaxelwith CsA showed that P-gp inhibition by CsA was maximal at a single doseof 10 mg/kg [58].

In another phase I study, patients received 1,000 mg GF120918 1 hourprior to oral paclitaxel [59]. The increase in systemic exposure topaclitaxel was of the same magnitude as in combination with CsA. Basedon the results of these phase I studies, phase II studies were initiatedto investigate whether repeated oral administration of paclitaxel wasfeasible and active. Oral paclitaxel was given b.i.d. once a week inseveral tumour types: as first- and second-line treatment in NSCLC [60],as first-line treatment in advanced gastric cancer [99], and assecond-line treatment in advanced breast cancer [100]. All patients weretreated with weekly oral paclitaxel b.i.d. in a dose of 90 mg/m². CsA,in a dose of 10 mg/kg, was given 30 minutes prior to every paclitaxeldose. In the patients with advanced NSCLC, the overall response rate(ORR) was 26% in 23 evaluable patients [60]. This is comparable with theearlier studies, as were the median time to progression of 3.5 monthsand median overall survival of 6 months. These studies, in which severalsingle agents such as vinorelbine, gemcitabine, and the taxanes wereused, revealed response rates between 8%-40% and median overall survivalranged from 6-11 months [61-66].

In advanced gastric cancer, chemotherapy is given with palliativeintent. Combination chemotherapy with agents such as 5-FU/doxorubicincombined with mitomycin or methotrexate, or theepirubicin/cisplatin/5-FU regimen are schedules that are frequently usedand have shown response rates between 20%-50% [67-70]. Paclitaxel hasalso shown anti-tumour activity in patients with advanced gastric cancer(ORR: 5%-23%) in first- and in second-line treatment [71-73]. The ORR inthis study was 32% in 24 evaluable patients. The toxicity profile ofthis b.i.d. weekly schedule is well manageable [99]. The most prevalenttoxicity in the group of patients with NSCLC was grade 3/4 neutropenia,which was observed in 54% of patients. This is comparable with thestandard every-3-week i.v. paclitaxel schedule [65, 66].

The prevalence of neurotoxicity was lower compared with the every-3-weekschedule, which may be explained by the lower peak plasma concentrationsof paclitaxel in this study. This was also observed in patients whoreceived the 24-hour infusion versus the 3-hour infusion of paclitaxel[74], although it can be questioned whether paclitaxel plasma levelsafter i.v. administration (thus in the presence of Cremophor EL) can becompared with those after oral paclitaxel (thus without Cremophor EL).

For docetaxel, a similar clinical proof-of-concept study was carried outin patients with solid tumours. Patients received one course of oraldocetaxel 75 mg/m² with or without a single oral dose of CsA 15 mg/kg.Pharmacokinetic results showed that coadministration of oral CsAresulted in a 7.3-fold increase of the systemic exposure of docetaxel.The apparent bioavailability of oral docetaxel increased from 8% withoutCsA to 90% with CsA [75]. This increase in systemic exposure can beexplained by inhibition of CYP3A4, as well as by P-gp inhibition in thegastrointestinal tract by CsA, but the magnitude of both mechanismscannot be determined exactly. The effect of CsA on the bioavailabilityof docetaxel was less pronounced in mice [49] compared with humans [75],but the reasons for this modest effect in mice are not clear. A phase IIstudy in advanced breast cancer with weekly oral docetaxel plus CsA wasalso performed. This schedule was given weekly for 6 weeks followed by a2-week rest. A weekly oral dose of 100 mg docetaxel was given, leadingto an AUC equivalent to a weekly i.v. dose of 40 mg/m², which wasreasonably well tolerated [76]. CsA was given 30 minutes prior to theintake of oral docetaxel in a dose of 15 mg/kg. The i.v. formulation ofdocetaxel was used as a drinking solution. In 25 patients evaluable forresponse, an ORR of 52% was noted.

The most frequently recorded toxicities were neutropenia, diarrhoea,nail toxicity, and fatigue. However, haematological toxicity seems to beless severe than after i.v. administration [77]. The response rate inthis study is in the upper range of results described in the literature[76-79].

The inter- and intra-patient variabilities in the AUC of docetaxel afteroral administration were in the same range as observed after i.v.administration of docetaxel (29%-53%) [80, 81].

The weekly or b.i.d. administration of an oral dose of CsA, incombination with oral docetaxel or paclitaxel, could result in renaltoxicity or infections due to immunosuppression [82]. Therefore, analternative drug to improve the clinical bioavailability of oraldocetaxel or paclitaxel would, in the present inventors view, bepreferred.

Intensive weekly oral schedules with taxanes are feasible and showclinically meaningful activity in advanced breast, gastric, and NSCLC.The oral schedule is convenient and has a favourable haematologicaltoxicity profile, and the non-haematological toxicity is acceptable.

The prior art appears to be primarily focused on inhibiting the actionof P-gp in order to improve the bioavailability and pharmacokineticproperties of anticancer drugs. This has been done using various drugs,for example, CsA and GF120918. It appears that P-gp was seen as the mostimportant protein to block in order to improve bioavailability of oraldrugs.

Accordingly, in a first aspect, the present invention provides apharmaceutical composition for oral administration comprising a taxaneand a CYP3A4 inhibitor, such as ritonavir, together with one or morepharmaceutically acceptable excipients.

The advantage of using ritonavir in combination with a taxane is thatthe oral bioavailability of the taxane is increased so that more drug isabsorbed from the intestines into the blood stream. This is due to theinhibition of CYP3A4 which stops the drug from being metabolised and theminor P-gp inhibiting properties. The ritonavir also reduces theelimination of the taxane from the body by inhibiting CYP3A4 metabolismin the liver. This means that a higher blood plasma level of the taxaneis reached for a longer period of time. For example, docetaxelmetabolites are less pharmacologically active than docetaxel itself.Therefore, by inhibiting metabolism of docetaxel, the mostpharmacologically active form is present in the bloodstream at a higherlevel and also for longer. This provides a greater therapeutic effect.As a result, it may be possible to reduce the amount of taxane per dose.Further, inhibition of CYP3A4 reduces interpatient variability inbioavailability and elimination due to differing levels of CYP activityin different patients.

The targeting and inhibition of CYP3A4 with ritonavir rather thantargeting P-gp improves the bioavailability of oral taxanes by stoppingtheir metabolism. This, on the whole, is a different approach to thatfollowed by the prior art.

Pharmaceutical compositions of this invention comprise any taxane, orpharmaceutically acceptable salts and esters thereof, and ritonavir (orpharmaceutically acceptable salts and esters thereof) together with anypharmaceutically acceptable carrier, adjuvant or vehicle.Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in the pharmaceutical compositions of this invention include, butare not limited to, ion exchangers, alumina, aluminium stearate,lecithin, serum proteins, such as human serum albumin, buffer substancessuch as phosphates, glycerine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat. The pharmaceutical compositions ofthis invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, a powder or coated granules. Suspensions,solutions and emulsions, preferably in an aqueous vehicle, may also beemployed. Tablets may be formulated to be immediate release, extendedrelease, repeated release or sustained release. They may also, oralternatively, be effervescent, dual-layer and/or coated tablets. Theextended release, repeated release and sustained release formulationscan be for one or both active ingredients. Tablets can be formed fromsolid dispersions or solid solutions of the taxane and/or ritonavir.Capsules may be formulated to be immediate release, extended release,repeated release or sustained release. They may be solid-filled orliquid-filled capsules. The extended release, repeated release andsustained release formulations can be for one or both activeingredients. Capsules can be formed from solid dispersions or solidsolutions of the taxane and/or ritonavir or the taxane and/or ritonavircan be dissolved or dispersed in a liquid. For example, a possiblesolvent for liquid filled capsules is triacetin. This appears to be aparticularly good solvent for paclitaxel. Aqueous solutions can be“ready to use”, prepared from a powder or powders, prepared from a soliddispersion or dispersions or by mixing solutions of the taxane andritonavir. The aqueous solutions may also comprise other pharmaceuticalexcipients, for example, polysorbate 80 and ethanol. In the case oftablets and capsules for oral use, carriers which are commonly usedinclude sucrose, cyclodextrins, polyethyleneglycols, polymethacrylates,polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates,mannitol, inulin, sugars (dextrose, galactose, sucrose, fructose orlactose), HPMC (hydroxypropylmethyl cellulose), PVP (polyvinylpyrrolidone) and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried corn starch. For tabletsand capsules, other pharmaceutical excipients that can be added arebinders, fillers, filler/binders, adsorbents, moistening agents,disintegrants, lubricants, glidants, surfactants and the like. Tabletsand capsules may be coated to alter the appearance or properties of thetablets and capsules, for example, to alter the taste or to colour coatthe tablet or capsule. When aqueous suspensions are administered orally,the active ingredient is combined with emulsifying and suspendingagents. If desired, certain sweetening and/or flavouring and/orcolouring agents may be added.

Solid dispersions or solid solutions of the taxane and ritonavir can beformed using any suitable method and may include carriers, for example,polymers. Such methods are well known to those skilled in the art [93,94]. The taxane and the ritonavir in the solid dispersion can be in anamorphous, crystalline or partly amorphous/partly crystalline state.Often, organic solvents are used in the preparation of soliddispersions. These can be any suitable organic solvent, for example, TBA(tertiary butyl alcohol), ethanol, methanol, DMSO (dimethyl sulfoxide)and IPA (iso-propyl alcohol). Any methods for removing organic and/oraqueous solvents from solid dispersion solutions can be used, forexample, freeze drying, spray drying, spray-freeze drying and vacuumdrying.

In compositions, particularly solid compositions, for oraladministration, the taxane and ritonavir may be present in the samedosage form, or may be present in separate dosage forms. If present inthe same dosage form, the taxane and ritonavir may be formulatedtogether, or may be present in separate compartments of amulti-compartment dosage form, such as a multi-layer tablet, or acompartmentalised capsule.

For the compositions comprising modified release formulations, forexample, extended release, repeated release and sustained releaseformulations, the aim is to maintain adequate blood levels of one orboth active ingredients for a prolonged period of time afteradministration.

A repeated release formulation, e.g. a tablet or capsule, is one whichis capable of releasing an adequate dose of taxane (e.g. docetaxel) andritonavir immediately (e.g. at time t=0 h) and releasing an additionalbooster dose of ritonavir later on (e.g. at time t=4 h when the Cmax ofritonavir is typically reached). This can be achieved, for example, byseparating the initial doses of docetaxel and ritonavir from the boosterdose of ritonavir by an enteric coating or a polymeric coatingcontaining enzymatically cleavable bonds which enable the coating to bebroken down and dissolved in the intestines. Alternatively, this may beachieved by filling a capsule with coated and uncoated granules, whereinthe coated granules contain only ritonavir and the uncoated granulescontain docetaxel and ritonavir. This could, of course, also be achievedby combining an immediate release docetaxel tablet/capsule with arepeated release tablet/capsule of ritonavir. Any suitable entericcoating can be used, for example, cellulose acetate phthalate, polyvinylacetate phthalate and suitable acrylic derivates, e.g.polymethacrylates.

In one embodiment, a second booster dose (thus a total of three doses)of ritonavir could be delivered by the same principle, i.e. repeatedrelease, some hours after the first booster dose (e.g. when the Cmax ofthe first booster dose of ritonavir is reached).

A sustained release formulation is one which is capable of, for example,releasing an adequate dose of taxane and an initial priming/loading doseof ritonavir followed by the slow release of a maintenance dose ofritonavir. For example, this could be achieved by a single oral dosageform of docetaxel and ritonavir or by combining an immediate releasetablet/capsule of docetaxel with a sustained release tablet/capsule ofritonavir.

Modified release formulations can, for example, utilise inert insolublematrices, hydrophilic matrices, ion-exchange resins, osmoticallycontrolled formulations and reservoir systems. A typical modifiedrelease system could, for example, consist of the following substances:active drug(s), release controlling agent(s) (e.g. matrix formers,membrane formers), matrix or membrane modifiers, solubiliser, pHmodifier, lubricant and flow aid, supplementary coatings and densitymodifiers [84]. Suitable inert excipients include dibasic calciumphosphate, ethyl cellulose, methacrylate copolymer polyamide,polyethylene, polyvinyl acetate. Suitable lipid excipients includecarnauba wax, acetyl alcohol, hydrogenated vegetable oils,microcrystalline waxes, mono- and triglycerides, PEG monostearate andPEG. Suitable hydrophilic excipients include alginates, carbopol,gelatin, hydroxypropylcellulose, hydroxypropyl methylcellulose andmethylcellulose [84].

In one embodiment of the invention, the composition comprising a taxaneand ritonavir may be formulated so that the ritonavir is releasedslightly earlier or faster than the taxane. This will have the effect ofinhibiting the CYP3A4 enzymes in the intestines before a substantialamount of the taxane has been released from the composition. Therefore,this will reduce the amount of the taxane that is broken down by theCYP3A4 enzymes before it reaches the bloodstream and, by virtue of theeffect of ritonavir on CYP3A4 in the liver, will also have the effect ofreducing the metabolism and elimination of taxane reaching thebloodstream during the early stages of absorption thereof. This effectis demonstrated by FIG. 1 which shows a trend that administration of theritonavir 60 mins before the docetaxel increases the oralbioavailability and AUC. Although this result is not statisticallysignificant in Example 2, this trend can be seen.

Taxanes are diterpene compounds which originate from plants of the genusTaxus (yews). However, some taxanes have now been producedsynthetically. Taxanes inhibit cell growth by stopping cell division andare used in treatment of cancer. They stop cell division by disruptingmicrotubule formation. They may also act as angiogenesis inhibitors. Theterm “taxane”, as used herein, includes all diterpene taxanes, whetherproduced naturally or artificially, functional derivatives andpharmaceutically acceptable salts or esters which bind to tubulin and/orare substrates for CYP3A4. Preferred taxanes are docetaxel, paclitaxel,BMS-275183, functional derivatives thereof and pharmaceuticallyacceptable salts or esters thereof. BMS-275183 is aC-3′-t-butyl-3′-N-t-butyloxycarbonyl analogue of paclitaxel [83]. Themost preferred taxane is docetaxel, a functional derivative thereof or apharmaceutically acceptable salt or ester thereof and, in particular,those derivatives which are substrates for CYP3A4.

Derivatives of taxanes containing groups to modify physiochemicalproperties are also included within the present invention. Thus,polyalkylene glycol (such as polyethylene glycol) or saccharideconjugates of taxanes, with improved or modified solubilitycharacteristics, are included.

The pharmaceutical composition of the present invention can comprise anysuitable amount of each of the taxane and ritonavir. Preferably, thecomposition comprises between about 0.1 mg and about 1000 mg of thetaxane. Preferably, the composition also comprises between about 0.1 mgand about 1200 mg of ritonavir. The amounts of each of the taxane andritonavir will depend on the intended frequency of administration of thecomposition. For example, the composition can be for administration on atri-daily, bi-daily or daily basis, every two days, weekly, every twoweeks, every three weeks or any other suitable dosing interval.Combinations of these dosage regimens can also be used, for example, thecomposition can be for bi-daily administration once every week or everytwo or three weeks. For example, paclitaxel or docetaxel can beadministered on a bi-daily basis once a week. The normal weekly dose issplit so that a subject takes, for example, half a dose in the morningand the other half in the evening once a week. This has the effect ofdecreasing the peak levels of the drug in plasma which can help toreduce side effects. It also increases the overall time of systemicexposure of the drug.

If the composition is for daily administration, the compositionpreferably comprises between about 0.1 mg and about 100 mg of thetaxane, more preferably, between about 5 mg and about 40 mg of thetaxane, more preferably, between about 5 mg and about 30 mg of thetaxane, more preferably, between about 10 mg and about 20 mg of thetaxane, and most preferably, about 15 mg of the taxane. Preferably, thecomposition also comprises between about 50 mg and about 1200 mg ofritonavir, more preferably, between about 50 mg and about 500 mg ofritonavir, more preferably, between about 50 mg and about 200 mg ofritonavir, and most preferably, about 100 mg of ritonavir.

If the composition is for weekly administration, the compositionpreferably comprises between about 30 mg and about 500 mg of the taxane,more preferably, between about 50 mg and about 200 mg of the taxane and,most preferably, about 100 mg of the taxane. Preferably, the compositionalso comprises between about 50 mg and about 1200 mg of ritonavir, morepreferably, between about 50 mg and about 500 mg of ritonavir, morepreferably, between about 50 mg and about 200 mg of ritonavir, and mostpreferably, about 100 mg of ritonavir.

Surprisingly, it has been found that using ritonavir at a low dose, forexample, 100 mg, still has the desired properties of enhancing thebioavailability of taxanes to give an enhanced therapeutic effect. Thismeans that a small dose of ritonavir can be used to have the desiredeffect, whilst minimising the risk of side effects.

The present invention also provides a composition comprising a taxaneand a CYP3A4 inhibitor, such as ritonavir, for use in therapy.

Furthermore, the present invention also provides a compositioncomprising a taxane and a CYP3A4 inhibitor, such as ritonavir for use inthe treatment of neoplastic disease.

The neoplastic disease treated by the present invention is preferably asolid tumour. The solid tumour is preferably selected from breast, lung,gastric, colorectal, head & neck, oesophageal, liver, renal, pancreatic,bladder, prostate, testicular, cervical, endometrial, ovarian cancer andnon-Hodgkin's lymphoma (NHL). The solid tumour is more preferablyselected from breast, gastric, ovarian, prostate, head & neck andnon-small cell lung cancer.

In one embodiment, the treatment of the neoplastic disease comprisesadministration of the composition and subsequently, after apredetermined period of time, administration of a booster dose ofritonavir. The booster dose is preferably administered between about 0hours and about 12 hours after the composition, more preferably, betweenabout 1 hour and about 10 hours after the composition, more preferably,between about 2 hours and about 8 hours after the composition, morepreferably, between about 3 hours and about 5 hours after thecomposition and, most preferably, about 4 hours after the composition.The booster dose is preferably between about 50 mg and about 1200 mg ofritonavir, more preferably, between about 50 mg and about 500 mg ofritonavir, more preferably, between about 50 mg and about 200 mg ofritonavir, and most preferably, about 100 mg of ritonavir.

Surprisingly, the administration of a booster dose of ritonavir has beenfound to provide a therapeutic level of the taxane in the bloodstreamfor a longer period of time thereby having a greater therapeutic effect.

In a related aspect, the present invention also provides a method oftreatment of a neoplastic disease comprising the administration, to asubject in need of such treatment, of an effective amount of a taxaneand a CYP3A4 inhibitor, such as ritonavir.

As with the composition above, the taxane can be any suitable taxane.Preferably, the taxane is selected from docetaxel, paclitaxel,BMS-275183, functional derivatives thereof and pharmaceuticallyacceptable salts or esters thereof and, more preferably, the taxane isdocetaxel, a functional derivative thereof or a pharmaceuticallyacceptable salt or ester thereof.

When the taxane and the ritonavir are being administered to the subject,they can be administered substantially simultaneously with each other.Alternatively, they can be administered separately from each other. Whenthey are administered separately, the ritonavir is preferablyadministered before the taxane and, more preferably, approximately 60minutes before the taxane.

“Substantially simultaneously”, as used herein, means administration ofthe taxane or ritonavir within approximately 20 minutes, more preferablywithin 15 minutes, more preferably within 10 minutes, even morepreferably within 5 minutes, most preferably within 2 minutes of theritonavir or taxane. Generally, the ritonavir should be administeredsimultaneously with or before the taxane. The ritonavir and taxane may,in some embodiments, be administered simultaneously, i.e. together inone formulation or simultaneously in two separate formulations.

Any suitable amount of the taxane or ritonavir can be administered inaccordance with the method. The dose of taxane and/or ritonavir can beadministered in a flat dose (i.e. the same for all patients regardlessof weight or body surface area) or a weight-based or body surfacearea-based dose. Preferably, the taxane and/or ritonavir is administeredin a flat dose. Preferably, between about 0.1 mg and about 1000 mg ofthe taxane is administered. Preferably, between about 0.1 mg and about1200 mg of ritonavir is administered. The amounts of each of the taxaneand ritonavir administered will depend on the intended frequency ofadministration of the taxane and ritonavir. For example, administrationcan be on a tri-daily, bi-daily or daily basis, every two days, weekly,every two weeks, every three weeks or any other suitable dosinginterval. Combinations of these dosage regimens can also be used, forexample, a bi-daily administration once every week or every two or threeweeks.

If the method involves daily administration of the taxane and ritonavir,preferably between about 0.1 mg and about 100 mg of the taxane isadministered, more preferably, between about 5 mg and about 40 mg of thetaxane is administered, more preferably, between about 5 mg and about 30mg of the taxane is administered, more preferably, between about 10 mgand about 20 mg of the taxane is administered, and most preferably,about 15 mg of the taxane. Preferably, between about 50 mg and about1200 mg of ritonavir is also administered, more preferably, betweenabout 50 mg and about 500 mg of ritonavir is administered, morepreferably, between about 50 mg and about 200 mg of ritonavir isadministered and, most preferably, about 100 mg of ritonavir isadministered.

If the method involves weekly administration of the taxane andritonavir, preferably between about 30 mg and about 500 mg of the taxaneis administered, more preferably, between about 50 mg and about 200 mgof the taxane is administered and, most preferably, about 100 mg of thetaxane is administered. Preferably, between about 50 mg and about 1200mg of ritonavir is also administered, more preferably, between about 50mg and about 500 mg of ritonavir is administered, more preferably,between about 50 mg and about 200 mg of ritonavir is administered and,most preferably, about 100 mg of ritonavir is administered.

The method can be for treating any neoplastic disease. Preferably, theneoplastic disease is a solid tumour. Preferably, the solid tumour isselected from breast, lung, gastric, colorectal, head & neck,oesophageal, liver, renal, pancreatic, bladder, prostate, testicular,cervical, endometrial, ovarian cancer and NHL. More preferably, thesolid tumour is selected from breast, ovarian, prostate, gastric, head &neck and non-small cell lung cancer.

Preferably, the method is used to treat a human subject.

In one embodiment, the method further comprises the administration of abooster dose of a CYP3A4 inhibitor, such as ritonavir a predeterminedperiod of time after the administration of the first dose of ritonavir(i.e. the dose of ritonavir combined with the dose of the taxane). Thebooster dose is preferably administered between about 0 hours and about12 hours after the composition, more preferably, between about 1 hourand about 10 hours after the composition, more preferably, between about2 hours and about 8 hours after the composition, more preferably,between about 3 hours and about 5 hours after the composition and, mostpreferably, about 4 hours after the composition. The booster dose ispreferably between about 50 mg and about 1200 mg of ritonavir, morepreferably, between about 50 mg and about 500 mg of ritonavir, morepreferably, between about 50 mg and about 200 mg of ritonavir, and mostpreferably, about 100 mg of ritonavir.

The present invention also provides a method of treatment of aneoplastic disease, the method comprising administering a compositioncomprising a taxane, and one or more pharmaceutically acceptableexcipients, to a subject receiving a CYP3A4 inhibitor, such as ritonavirsimultaneously, separately or sequentially with the taxane.

The present invention further provides a method of treatment of aneoplastic disease, the method comprising administering a compositioncomprising a CYP3A4 inhibitor, such as ritonavir, and one or morepharmaceutically acceptable excipients, to a subject receiving a taxanesimultaneously, separately or sequentially with the CYP3A4 inhibitor,such as ritonavir.

Additionally, the present invention provides a kit comprising a firstpharmaceutical composition comprising a taxane and a secondpharmaceutical composition comprising a CYP3A4 inhibitor, such asritonavir, the first and second pharmaceutical compositions beingsuitable for simultaneous, separate or sequential administration for thetreatment of neoplastic disease.

In one embodiment, the kit may further comprise a third pharmaceuticalcomposition comprising a CYP3A4 inhibitor, such as ritonavir beingsuitable for administration subsequent to the second pharmaceuticalcomposition comprising a CYP3A4 inhibitor, such as ritonavir. It will beappreciated that the second and third pharmaceutical compositions in thekit, each comprising a CYP3A4 inhibitor, such as ritonavir, may be unitdose forms of substantially the same composition.

Alternatively, the kit may comprise a first pharmaceutical compositioncomprising a taxane and a CYP3A4 inhibitor, such as ritonavir, for thetreatment of neoplastic disease. In this case, the kit may furthercomprise a second pharmaceutical composition comprising a CYP3A4inhibitor, such as ritonavir being suitable for administrationsubsequent to the first pharmaceutical composition.

Further, the present invention provides a composition comprising ataxane, and one or more pharmaceutically acceptable excipients, for usein the treatment of neoplastic disease in a subject receiving a CYP3A4inhibitor, such as ritonavir simultaneously, separately or sequentiallywith the taxane.

Further still, the present invention provides a composition comprising aCYP3A4 inhibitor, such as ritonavir, and one or more pharmaceuticallyacceptable excipients, for use in the treatment of neoplastic disease ina subject receiving taxane simultaneously, separately or sequentiallywith the CYP3A4 inhibitor, such as ritonavir.

It will be appreciated by one skilled in the art that any or all of thepreferred features described above in relation to compositions, methodsor kits employing ritonavir are equally applicable to those employingother CYP3A4 inhibitors, for example, grapefruit juice or St. John'swort (or components of either), lopinavir or imidazole compounds, suchas ketoconazole.

Another problem associated with the prior art is that it has not beenpossible to develop an oral composition comprising a taxane in which thetaxane has a high bioavailability with low variability. Clinical studieswith oral paclitaxel [e.g. 3] and oral docetaxel [e.g. 75] have beenexecuted where the i.v. taxane formulations (also containing excipientssuch as Cremophor EL and ethanol, or polysorbate 80 and ethanol) wereingested orally. Nausea, vomiting and an unpleasant taste are frequentlyreported by the patients.

As discussed earlier, Chen et al. [95] tried using a solid dispersion ofdocetaxel in combination with poloxamer 188 or PVP-K30 to improve thesolubility and dissolution rate of docetaxel. Poloxamer increased thesolubility of docetaxel to about 3.3 μg/ml after 20 minutes and to amaximum of about 5.5 μg/ml after about 120 minutes when a docetaxel topoloxamer ratio of 5:95 was used (see FIG. 7 in Chen paper). PVP-K30increased the solubility of docetaxel to about 0.8 μg/ml after 20minutes and to a maximum of about 4.2 μg/ml after about 300 minutes (seeFIG. 2). In order to achieve good oral bioavailability, a drug must havea relatively high solubility and dissolution rate so that there is ahigh enough amount of the drug in solution with the first about 0.5 to1.5 hours.

In another aspect, the present invention provides a solid pharmaceuticalcomposition for oral administration comprising a substantially amorphoustaxane, a hydrophilic, and preferably polymeric, carrier and asurfactant.

The advantage provided by the composition of this aspect is that thesolubility of the taxane is increased by a surprising degree. Further,the rate of dissolution of the taxane is also increased to a surprisingdegree. Both of these factors result in a significant increase in thebioavailability of the taxane. It is thought that this is due, at leastin part, to the taxane being in an amorphous state. Crystalline taxaneshave very low solubilities. Further, in clinical trials, it was foundthat the oral compositions of the invention gave a high AUC, and aninter-individual variability which was significantly lower than theinter-individual variability demonstrated by a liquid formulation. Thisprovides a much more predictable taxane exposure which is very desirablefrom a safety perspective in oral chemotherapy regimens. Theintra-individual variability also appeared to be significantly lower. Afurther advantage is that the oral composition of the invention appearsto be at least equally or better tolerated (i.e. in terms of sideeffects) than a liquid oral taxane solution.

An advantage provided by the carrier is that it helps to maintain thetaxane in an amorphous state when it is placed in aqueous media. Thishelps to stop the taxane from crystallising or increases the length oftime before the taxane starts to crystallise in solution. Therefore, thesolubility and dissolution rate of the taxane remain high. Further, thecarrier gives good physical and chemical stability to the composition.It helps to prevent the degradation of the taxane and also helps toprevent the substantially amorphous taxane from changing to a morecrystalline structure over time in the solid state. The good physicalstability ensures the solubility of the taxane remains high.

The surfactant also helps to maintain the taxane in an amorphous statewhen placed in aqueous media and, surprisingly, substantially increasesthe solubility of the taxane compared to compositions comprising anamorphous taxane and a carrier.

The term “substantially amorphous” means that there should be little orno long range order of the position of the taxane molecules. Themajority of the molecules should be randomly orientated. A completelyamorphous structure has no long range order and contains no crystallinestructure whatsoever; it is the opposite of a crystalline solid.However, it can be hard to obtain a completely amorphous structure forsome solids. Therefore, many “amorphous” structures are not completelyamorphous but still contain a certain amount of long range order orcrystallinity. For example, a solid may be mainly amorphous but havepockets of crystalline structure or may contain very small crystals sothat it is bordering on being truly amorphous. Therefore, the term“substantially amorphous” encompasses solids which have some amorphousstructure but which also have some crystalline structure as well. Thecrystallinity of the substantially amorphous taxane should be less than50%. Preferably, the crystallinity of the substantially amorphous taxaneis less than 40%, even more preferably, less than 30%, more preferablystill, less than 25%, even more preferably, less than 20%, morepreferably still, less than 15%, even more preferably, less than 12.5%,more preferably still, less than 10%, even more preferably, less than7.5%, more preferably still, less than 5% and most preferably, less than2.5%. Since crystalline taxanes have low solubility, the lower thecrystallinity of the substantially amorphous taxane, the better thesolubility of the substantially amorphous taxane.

The substantially amorphous taxane can be prepared in any suitablemanner and techniques would be apparent to those skilled in the art. Forexample, it may be prepared using a solvent evaporation method orlyophilisation. Preferably, the amorphous taxane is prepared bylyophilisation. Surprisingly, it has been found that preparing theamorphous taxane using lyophilisation results in the composition havinga better solubility and dissolution rate compared to an evaporationmethod. This is thought to be due to the lyophilisation method producinga more amorphous taxane compared to the solvent evaporation method.

The composition for oral administration is in a solid form. The solidcomposition can be in any suitable form as long as the taxane is in asubstantially amorphous state. For example, the composition can comprisea physical mixture of amorphous taxane, carrier and surfactant.Preferably, the taxane and carrier are in the form of a soliddispersion. The term “solid dispersion” is well known to those skilledin the art and means that the taxane is partly molecularly dispersed inthe carrier. More preferably, the taxane and carrier are in the form ofa solid solution. The term “solid solution” is well known to thoseskilled in the art and means that the taxane is substantially completelymolecularly dispersed in the carrier. It is thought that solid solutionsare more amorphous in nature than solid dispersions. Methods ofpreparing solid dispersions and solid solutions are well known to thoseskilled in the art [93, 94]. Using these methods, both the taxane andcarrier are in an amorphous state. When the taxane and carrier are inthe form of a solid dispersion or solution, the solubility anddissolution rate of the taxane is greater than a physical mixture ofamorphous taxane and carrier. It is thought that, when the taxane is ina solid dispersion or solution, the taxane is in a more amorphous statecompared to amorphous taxane on its own. It is thought that this resultsin the improved solubility and dissolution. The crystallinity of thesolid dispersion or solution should be less than 50%. Preferably, thecrystallinity of the solid dispersion or solution is less than 40%, evenmore preferably, less than 30%, more preferably still, less than 25%,even more preferably, less than 20%, more preferably still, less than15%, even more preferably, less than 12.5%, more preferably still, lessthan 10%, even more preferably, less than 7.5%, more preferably still,less than 5% and most preferably, less than 2.5%.

When the taxane and carrier are in a solid dispersion, the surfactantcan be in a physical mixture with the solid dispersion or solution.Preferably, however, the composition comprises a taxane, carrier andsurfactant in the form of a solid dispersion or, more preferably, asolid solution. The advantage of having all three components in a soliddispersion or solution is that it enables the use of a lower amount ofsurfactant to achieve the same improvement in solubility and dissolutionrate.

In one embodiment, the composition can be contained in a capsule fororal administration. The capsule can be filled in a number of differentways. For example, the amorphous taxane may be prepared bylyophilisation, powdered, mixed with the carrier and surfactant, andthen dispensed into the capsule. In an alternative preferableembodiment, the amorphous taxane is prepared by lyophilisation of ataxane solution in a capsule for oral administration. The taxanesolution containing the required amount of taxane is dispensed into thecapsule and then lyophilised whilst contained in the capsule. This makesit easier to dispense the required amount of taxane into the capsule asit is easier to dispense liquids rather than powders. It also eliminatesa capsule filling step making the process more efficient. Powderedcarrier and surfactant can then be added. Preferably, the capsule is anHPMC capsule.

If the taxane and carrier are in the form of a solid dispersion orsolution, the solution containing the taxane and carrier is preferablydispensed into the capsule and then lyophilised whilst in the capsule.In this way, the solid dispersion or solution is prepared bylyophilisation of a taxane and carrier solution in a capsule for oraladministration. This again eliminates a capsule filling step. Powderedsurfactant can then be added.

If the taxane, carrier and surfactant are in the form of a soliddispersion or solution, the solution containing the taxane, carrier andsurfactant is preferably dispensed into the capsule and then lyophilisedwhilst in the capsule. In this way, the solid dispersion or solution isprepared by lyophilisation of a taxane, carrier and surfactant solutionin a capsule for oral administration. This again eliminates a capsulefilling step and eliminates the need to handle powders which can beproblematic.

The taxane of the composition can be any suitable taxane as definedabove. Preferably, the taxane is selected from docetaxel, paclitaxel,BMS-275183, functional derivatives thereof and pharmaceuticallyacceptable salts or esters thereof. More preferably, the taxane isselected from docetaxel, paclitaxel, functional derivatives thereof andpharmaceutically acceptable salts or esters thereof.

The hydrophilic, and preferably polymeric, carrier of the composition isan organic, and preferably polymeric, compound capable of at leastpartial dissolution in aqueous media at pH 7.4 and/or capable ofswelling or gelation in such aqueous media. The carrier can be anysuitable hydrophilic, and preferably polymeric, carrier which ensuresthat the taxane remains in an amorphous state in the composition andincreases the solubility and dissolution rate of the taxane. Preferably,the carrier is selected from: polyvinylpyrrolidone (PVP); polyethyleneglycol (PEG); polyvinylalcohol (PVA); crospovidone (PVP-CL);polyvinylpyrrolidone-polyvinylacetate copolymer (PVP-PVA); cellulosederivatives such as methylcellulose, hydroxypropylcellulose,carboxymethylethylcellulose, hydroxypropylmethylcellulose (HPMC),cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate;polyacrylates; polymethacrylates; sugars, polyols and their polymerssuch as mannitol, sucrose, sorbitol, dextrose and chitosan; andcyclodextrins. More preferably, the carrier is selected from PVP, PEGand HPMC, and most preferably, the carrier is PVP.

If the carrier is PVP, it can be any suitable PVP [98] to act as acarrier and to help keep the taxane in an amorphous state. For example,the PVP may be selected from PVP-K12, PVP-K15, PVP-K17, PVP-K25,PVP-K30, PVP-K60, PVP-K90 and PVP-K120. Preferably, the PVP is selectedfrom PVP-K30, PVP-K60 and PVP-K90.

The composition can contain any suitable amount of the carrier relativeto the amorphous taxane so that the carrier maintains the amorphoustaxane in its amorphous state. Preferably, the taxane to carrier weightratio is between about 0.01:99.99 w/w and about 75:25 w/w. Morepreferably, the taxane to carrier weight ratio is between about0.01:99.99 w/w and about 50:50 w/w, even more preferably, between about0.01:99.99 w/w and about 40:60 w/w, more preferably still, between about0.01:99.99 w/w and about 30:70 w/w, even more preferably, between about0.1:99.9 w/w and about 20:80 w/w, more preferably still, between about1:99 w/w and about 20:80 w/w, even more preferably, between about2.5:97.5 w/w and about 20:80 w/w, more preferably still, between about2.5:97.5 w/w and about 15:85 w/w, even more preferably, between about5:95 w/w and about 15:85 w/w and most preferably, about 10:90 w/w.

The surfactant can be any suitable pharmaceutically acceptablesurfactant and such surfactants are well known to those skilled in theart. Preferably, the surfactant is selected from triethanolamine,sunflower oil, stearic acid, monobasic sodium phosphate, sodium citratedihydrate, propylene glycol alginate, oleic acid, monoethanolamine,mineral oil and lanolin alcohols, methylcellulose, medium-chaintriglycerides, lecithin, hydrous lanolin, lanolin, hydroxypropylcellulose, glyceryl monostearate, ethylene glycol pamitostearate,diethanolamine, lanolin alcohols, cholesterol, cetyl alcohol,cetostearyl alcohol, castor oil, sodium dodecyl sulphate (SDS), sorbitanesters (sorbitan fatty acid esters), polyoxyethylene stearates,polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oilderivatives, polyoxyethylene alkyl ethers, poloxamer, glycerylmonooleate, docusate sodium, cetrimide, benzyl bezoate, benzalkoniumchloride, benzethonium chloride, hypromellose, non-ionic emulsifyingwax, anionic emulsifying wax and triethyl citrate. More preferably, thesurfactant is selected from sodium dodecyl sulphate (SDS), sorbitanesters (sorbitan fatty acid esters), polyoxyethylene stearates,polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oilderivatives, polyoxyethylene alkyl ethers, poloxamer, glycerylmonooleate, docusate sodium, cetrimide, benzyl bezoate, benzalkoniumchloride, benzethonium chloride, hypromellose, non-ionic emulsifyingwax, anionic emulsifying wax and triethyl citrate. Most preferably, thesurfactant is SDS.

Any suitable amount of surfactant can be used in the composition inorder to improve the solubility and dissolution rate of the taxane.Preferably, the weight ratio of surfactant, to taxane and carriercombined, is between about 1:99 w/w and about 50:50 w/w, morepreferably, between about 1:99 w/w and about 44:56 w/w, even morepreferably, between about 1:99 w/w and about 33:67 w/w, more preferablystill, between about 2:98 w/w and about 33:67 w/w, even more preferably,between about 2:98 w/w and about 17:83 w/w, more preferably still,between about 5:95 w/w and about 17:83 w/w and most preferably, about9:91 w/w.

Alternatively, the weight ratio of surfactant to taxane is preferablybetween about 1:100 w/w and about 60:1 w/w, more preferably, betweenabout 1:50 w/w and about 40:1 w/w, even more preferably, between about1:20 w/w and about 20:1 w/w, more preferably still, between about 1:10w/w and about 10:1 w/w, even more preferably, between about 1:5 w/w andabout 5:1 w/w, more preferably still, between about 1:3 w/w and about3:1 w/w, even more preferably, between about 1:2 w/w and about 2:1 w/wand most preferably, about 1:1 w/w.

The unit dose of the taxane contained in the composition will depend onthe intended frequency of administration of the composition. Suitabledosages and frequency of administration are discussed above in relationto the taxane and ritonavir composition.

In one embodiment, the composition comprises an enteric coating.Suitable enteric coatings are described above. An enteric coatingprevents the release of the taxane in the stomach and thereby preventsacid-mediated degradation of the taxane. Furthermore, it enablestargeted delivery of the taxane to the intestines where the taxane isabsorbed, thus ensuring that the limited time during which the taxane ispresent in solution (before crystallisation takes place) is only spentat sites where absorption is possible.

In one embodiment, the composition may further comprise one or moreadditional pharmaceutically active ingredients. Preferably, one or moreof the additional pharmaceutically active ingredients is a CYP3A4inhibitor. Suitable CYP3A4 inhibitors are discussed above. Preferably,the CYP3A4 inhibitor is ritonavir.

The pharmaceutical composition may comprise additional pharmaceuticallyacceptable adjuvants and vehicles which are well known to those skilledin the art. Pharmaceutically acceptable adjuvants and vehicles that maybe used in the pharmaceutical compositions of this invention include,but are not limited to, ion exchangers, alumina, aluminium stearate,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycerine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate and wool fat.

The pharmaceutical compositions can be orally administered in any orallyacceptable dosage form including, but not limited to, capsules, tablets,a powder or coated granules. Tablets may be formulated to be immediaterelease, extended release, repeated release or sustained release. Theymay also, or alternatively, be effervescent, dual-layer and/or coatedtablets. Capsules may be formulated to be immediate release, extendedrelease, repeated release or sustained release. Lubricating agents, suchas magnesium stearate, are also typically added. For oral administrationin a capsule form, useful diluents include lactose and dried cornstarch. For tablets and capsules, other pharmaceutical excipients thatcan be added are binders, fillers, filler/binders, adsorbents,moistening agents, disintegrants, lubricants, glidants, and the like.Tablets and capsules may be coated to alter the appearance or propertiesof the tablets and capsules, for example, to alter the taste or tocolour coat the tablet or capsule.

Other pharmaceutically acceptable additives which may be added to thecomposition are well known to those skilled in the art, some of whichare discussed above with regard to the composition according to thefirst aspect of the invention.

The present invention also provides the above composition for use intherapy.

Further, the present invention provides the above composition for use inthe treatment of neoplastic disease. Suitable neoplastic diseases arediscussed above.

The present invention also provides a method of treatment of aneoplastic disease, the method comprising the administration, to asubject in need of such treatment, of an effective amount of the abovecomposition.

Preferably, the method is used to treat a human subject.

It will be appreciated by one skilled in the art that the composition ofthe invention comprising a substantially amorphous taxane and carriercan be used, in the methods described above relating to the use of ataxane and a CYP3A4 inhibitor or ritonavir where appropriate.

In another aspect, the present invention provides a pharmaceuticalcomposition for oral administration comprising a substantially amorphoustaxane and a carrier, wherein the substantially amorphous taxane isprepared by lyophilisation.

The advantage provided by this composition is that it provides increasedsolubility of the taxane and also an increased dissolution rate. It isthought that this is because the lyophilisation method produces a moreamorphous taxane compared to other methods of producing amorphoustaxanes. It is thought that the more amorphous nature of the taxaneprovides the increased solubility and dissolution rate.

Additional optional features of the composition are the same as for thecomposition comprising an amorphous taxane, a carrier and a surfactant.For example, the composition comprising a substantially amorphous taxaneand a carrier, wherein the substantially amorphous taxane is prepared bylyophilisation, preferably further comprises a surfactant. The preferredembodiments of the taxane, the carrier, the crystallinity of the taxane,the ratio of taxane to carrier, the state of the taxane and carrier,etc. are as defined above.

The present invention will now be described by way of example only withreference to the accompanying figures in which:

FIG. 1 is a graph showing docetaxel plasma concentration against time,comparing oral administration with ritonavir (RTV) (simultaneous, andwith ritonavir given 60 mins prior to docetaxel) to i.v. administration(without ritonavir); Oral docetaxel dose: 100 mg. The commerciallyavailable i.v. docetaxel formulation (Taxotere®; 2 ml=80 mg docetaxel;excipient polysorbate 80) was diluted with ethanol 95%:water (13:87) toprovide a 10 mg/ml docetaxel solution which the patients drank (10 ml ofthe 10 mg/ml solution) with 100 ml of tap water. Ritonavir dose: 1capsule with 100 mg ritonavir (Norvir®).

FIG. 2 is a graph showing ritonavir plasma concentration against time,comparing oral administration of ritonavir (dose 100 mg; Norvir®,capsule) at the same time as oral docetaxel or 60 mins before oraldocetaxel. T=0 is when docetaxel is administered. Therefore, the firstpart of the curve corresponding to ritonavir administered beforedocetaxel, is not visible. Oral docetaxel dose: 100 mg. The commerciallyavailable i.v. docetaxel formulation (Taxotere®; 2 ml=80 mg docetaxel;excipient polysorbate 80) was diluted with ethanol 95%:water (13:87) toprovide a 10 mg/ml docetaxel solution which the patients drank (10 ml ofthe 10 mg/ml solution) with 100 ml of tap water. Ritonavir dose: 1capsule with 100 mg ritonavir (Norvir®).

FIG. 3 is a pharmacokinetic model of oral docetaxel in combination withritonavir (RTV). The different compartments in the pharmacokinetic modelare as follows:

C1—gastrointestinal tract (input compartment of oral docetaxel)

C2—central compartment (docetaxel)

C3—first peripheral compartment (docetaxel)

C4—second peripheral compartment (docetaxel)

C5—gastrointestinal tract (input compartment of ritonavir)

C6—central compartment (ritonavir)

C7—active CYP3A4 enzyme

C8—inactive CYP3A4 enzyme;

FIG. 4 is a graph showing, for a number of subjects, each linerepresenting one subject, the relative amount of active CYP3A4 enzymeagainst time for oral docetaxel in combination with ritonavir;

FIG. 5 shows the results of a dissolution test of paclitaxel soliddispersions versus paclitaxel physical mixtures (conditions: 900 mL WfI,37° C., 75 rpm);

FIG. 6 shows the results of a dissolution test of paclitaxel (PCT) soliddispersion capsules with and without sodium dodecyl sulphate(conditions: 900 mL WfI, 37° C., 75 rpm);

FIG. 7 shows the results of a dissolution test of paclitaxel soliddispersions with sodium dodecyl sulphate incorporated in the soliddispersion or added to the capsule (conditions: 500 mL WfI, 37° C., 75rpm (100 rpm for SDS added to the capsules));

FIG. 8 shows the results of a dissolution test of paclitaxel soliddispersions with various carriers (conditions: 500 mL WfI, 37° C., 100rpm);

FIG. 9 shows the results of a solubility test of paclitaxel/PVP-K17solid dispersions with various drug-carrier ratios (conditions: 25 mLWfI, 37° C., 7200 rpm);

FIG. 10 shows the results of a dissolution test of paclitaxel soliddispersions in various media (conditions: 500 mL FaSSIF (light grey),37° C., 75 rpm; or 500 mL SGF_(sp) and 629 mL SIF_(sp), 37° C., 75 rpm(dark grey));

FIG. 11 shows the docetaxel solubility of five different formulations(see table 15). A: anhydrous docetaxel; B: amorphous docetaxel; C:physical mixture of anhydrous docetaxel, PVP-K30 and SDS; D: physicalmixture of amorphous docetaxel, PVP-K30 and SDS; E: solid dispersion ofamorphous docetaxel, PVP-K30 and SDS (dissolution conditions: ±6 mgdocetaxel, 25 mL WfI, 37° C., 720 rpm);

FIG. 12 shows docetaxel solubility of solid dispersions with differentcarriers (see table 15). E: Solid dispersion of amorphous docetaxel,PVP-K30 and SDS; F: Solid dispersion of amorphous docetaxel, HPβ-CD andSDS. (Dissolution conditions: ±6 mg Docetaxel, 25 mL WfI, 37° C., 720rpm);

FIG. 13 shows docetaxel solubility of solid dispersions with PVP ofvarious chain lengths (see table 15). E: solid dispersion of amorphousdocetaxel, PVP-K30 and SDS; G: solid dispersion of amorphous docetaxel,PVP-K12 and SDS; H: solid dispersion of amorphous docetaxel, PVP-K17 andSDS; I: solid dispersion of amorphous docetaxel, PVP-K25 and SDS; J:solid dispersion of amorphous docetaxel, PVP-K90 and SDS. (Dissolutionconditions: ±6 mg Docetaxel, 25 mL WfI, 37° C., 720 rpm);

FIG. 14 shows docetaxel solubility of solid dispersions with variousdrug loads (see table 15). E: 1/11 docetaxel; K: 5/7 docetaxel; L: 1/3docetaxel; M: 1/6 docetaxel; N: 1/21 docetaxel. (Dissolution conditions:±6 mg Docetaxel, 25 mL WfI, 37° C., 720 rpm);

FIG. 15 shows the dissolution results in terms of the relative amount ofdocetaxel dissolved of a solid dispersion of docetaxel, PVP-K30 and SDS,compared to literature data of a solid dispersion of docetaxel andPVP-K30 [Chen et al., 95];

FIG. 16 shows the dissolution results in terms of the absolute amount ofdocetaxel dissolved of a solid dispersion of docetaxel, PVP-K30 and SDS,compared to literature data of a solid dispersion of docetaxel andPVP-K30 [Chen et al., 95];

FIG. 17 shows the results of a dissolution test of docetaxel capsules(15 mg docetaxel (DXT) per capsule with PVP-K30+SDS) compared withliterature data (Chen et al. [95].

FIG. 18 shows the dissolution results in terms of the absolute amount ofdocetaxel dissolved of a solid dispersion of docetaxel, PVP-K30 and SDS.The dissolution test was carried out in Simulated Intestinal Fluid sinePancreatin (SIFsp);

FIG. 19 shows the dissolution results in terms of the relative amount ofdocetaxel dissolved of a solid dispersion of docetaxel, PVP-K30 and SDS.The dissolution test was carried out in Simulated Intestinal Fluid sinePancreatin (SIFsp);

FIG. 20 shows the pharmacokinetic curves of a patient who receiveddocetaxel and ritonavir simultaneously in a first cycle. In the secondcycle, the patient received docetaxel and ritonavir simultaneously att=0 and then an additional booster dose of ritonavir at t=4 h;

FIG. 21 shows the pharmacokinetic curves of four patients who received aliquid formulation of docetaxel and/or a solid dispersion comprisingdocetaxel (referred to as MODRA);

FIG. 22 shows the pharmacokinetic curves of patients receiving theliquid oral formulation of docetaxel compared to the patients receivingthe solid oral formulation of docetaxel (MODRA); and

FIG. 23 shows pharmacokinetic curves after i.v. and oral administrationof docetaxel. Both i.v. and oral docetaxel administration was combinedwith administration of ritonavir. N.B. The calculated bioavailability iscorrected for the administered dose.

EXAMPLE 1

A 100 mg ritonavir dose was combined with a 100 mg docetaxel dose andorally administered simultaneously to 22 patients. A comparison was madewith i.v. administered docetaxel (100 mg) (Taxotere®) given as a 1 houri.v. infusion (standard procedure) (without ritonavir).

Oral ritonavir: 1 capsule with 100 mg ritonavir (Norvir®). Oraldocetaxel dose: 100 mg. The commercially available i.v. docetaxelformulation (Taxotere®; 2 ml=80 mg docetaxel; excipient polysorbate 80)was diluted with ethanol 95%:water (13:87) to provide a 10 mg/mldocetaxel solution which the patients drank (10 ml of the 10 mg/mlsolution) with 100 ml of tap water.

The pharmacokinetic data that were obtained are as follows:

AUC docetaxel oral without ritonavir 0.29 ± 0.26 (mg · h/L)  AUCdocetaxel oral with ritonavir 2.4 ± 1.5 (mg · h/L) AUC docetaxelintravenous without ritonavir 1.9 ± 0.4 (mg · h/L)

The results show a dual effect of ritonavir on both docetaxel absorptionand elimination. Docetaxel AUC increases 8.2 fold when given orally incombination with ritonavir. Surprisingly, the exposure is even higherthan that reached after intravenous administration reflecting theadditional ritonavir effect on inhibition of docetaxel elimination.

Conclusions

The concept has been clearly proven in patients that ritonavir canincrease the systemic exposure of oral docetaxel to levels that arecomparable to or even higher than the levels after intravenousadministration of docetaxel at the same dose level. The combinationappears to be safe with very favourable pharmacokinetic characteristics.

EXAMPLE 2

Treatment of solid malignancies with the oral combination of docetaxeland ritonavir.

Patients were randomized into two treatment groups, X and Y. Group Xreceived, in the first week, 100 mg of ritonavir followed 60 minuteslater by 100 mg oral docetaxel and, in the second week, these patientsreceived 100 mg ritonavir and 100 mg oral docetaxel simultaneously.Patients in group Y received, in the first week, 100 mg ritonavir and100 mg oral docetaxel simultaneously and, in the second week, 100 mgritonavir followed 60 minutes later by 100 mg oral docetaxel. Bothgroups X and Y received 100 mg i.v. docetaxel (Taxotere®; standardprocedure; as 1 hour infusion) without ritonavir 15 days after thecommencement of oral administration.

Oral docetaxel dose: 100 mg. The commercially available i.v. docetaxelformulation (Taxotere®; 2 ml=80 mg docetaxel; excipient polysorbate 80)was diluted with ethanol 95%:water (13:87) to provide a 10 mg/mldocetaxel solution which the patients drank (10 ml of the 10 mg/mlsolution) with 100 ml of tap water. Ritonavir dose: 1 capsule with 100mg ritonavir (Norvir®).

The pharmacokinetic results are given below:

TABLE 1A DOCETAXEL AUC (mg × h/L) F(%)¹ Simul- 60 min IV day Simul- 60min Patient taneous interval 15 taneous interval 101 (X) 5.6 4.1 1.7 329241 102 (Y) 1.6 2.6 1.8 89 144 103 (Y) 2.2 4.6 1.8 122 256 105 (X) 2.83.3 2.1 133 157 106 (Y) 2.4 3.9 1.4 171 279 107 (Y) 2.4 2.1 2.6 92 81108 (X) 1.1 1.4 1.4 79 100 110 (X) 0.7 0.6 2.2 32 27 Mean ± SD 2.4 ± 1.52.8 ± 1.4 1.9 ± 0.4 131 ± 90 161 ± 91 ¹F (apparent) determined by(AUCpo/AUC iv) × (dose iv/dose po) × 100% TABLE 1B DOCETAXEL Cmax (mg/L)Tmax (h) Simul- 60 min IV day Simul- 60 min IV day Patient taneousinterval 15 taneous interval 15 101 (X) 0.71 0.58 1.47 3.3 3.0 1.0 102(Y) 0.21 0.42 1.52 4.0 2.0 1.0 103 (Y) 0.20 0.72 1.3 4.0 3.0 0.8 105 (X)0.36 0.34 1.6 4.0 4.0 1.0 106 (Y) 0.42 0.91 1.1 2.0 2.0 0.8 107 (Y) 0.260.50 1.5 3.0 1.5 1.0 108 (X) 0.26 0.19 1.0 2.1 3.0 0.8 110 (X) 0.10 0.111.6 1.0 1.5 0.8 Mean ± SD 0.32 ± 0.2 0.47 ± 0.3 1.4 ± 0.2 2.9 ± 1.1 2.5± 0.9 0.9 ± 0.1

Conclusions

There is no significant difference between simultaneous administrationof docetaxel and ritonavir compared with ritonavir administered 60minutes before the docetaxel. The AUC for oral administration is greaterthan the AUC for intravenous administration (see FIG. 1). This isexplained by the effects of ritonavir on inhibition of docetaxelelimination.

Remarks

This clinical study was executed with relatively low doses of docetaxel,but yielding high AUC values (2.4±1.5 mg·h/L; 100 mg docetaxel) andwhich are even higher than the AUC values after intravenousadministration of the same dose. With that, it has to be realised thatthe distribution volume after the oral route is larger (shortly afteradministration) than after the intravenous route because thepharmaceutical vehicle, present after intravenous administration but notreaching the systemic circulation after oral administration, limitstissue distribution of docetaxel. The inventors have built apharmacokinetic model to understand these effects (see below). The modelalso demonstrates that the ritonavir effect on docetaxel elimination hasgone when ritonavir is not present anymore in the bloodstream. Ritonavirinhibits docetaxel clearance down to 35% of the level thereof in theabsence of ritonavir.

Compared to the doses used in the prior art preclinical study in mice,this clinical study used 100 mg ritonavir and 100 mg docetaxel whereasthe pre-clinical study in mice used 12.5 mg/kg ritonavir and 10-30 mg/kgdocetaxel. Docetaxel doses of 10-30 mg/kg are extremely toxic (lifethreatening) in humans. Ritonavir doses of 12.5 mg/kg are substantiallyhigher than would normally be used in humans to inhibit CYP3A4.

In the prior art preclinical study, ritonavir was given 30 minutes inadvance of docetaxel. In the clinical study the drugs were alsoadministered simultaneously with no significant difference for theimprovement in docetaxel pharmacokinetics, between simultaneous and 60minutes prior administration of ritonavir. This indicates that bothdrugs can be given in a single pharmaceutical form (e.g. tablet, capsuleor drinking solution containing both docetaxel and ritonavir).

The docetaxel AUC values (2.4±1.5 mg·h/L) obtained (with 100 mgdocetaxel dose) when co-administered with 100 mg ritonavir, can beconsidered therapeutically active in a weekly schedule, for example, inmetastatic breast cancer. This compares well with an earlier phase IItrial where 100 mg docetaxel was given orally with CsA at a dose of 15mg/kg, in a weekly schedule and leading to an overall response rate of50% of patients with metastatic breast cancer, with docetaxel AUCs ofabout 2.3 mg·h/L.

Ritonavir pharmacokinetic data are given below for completeness (seeFIG. 2):

TABLE 2 RITONAVIR AUC (mg · h/L) 60 min Cmax (mg/L) 60 min Tmax (h) 60min Patient Simultaneous interval Simultaneous interval Simultaneousinterval 101 (X) 23.2 11.8 3.1 1.3 3.3 0.3 102 (Y) 7.3 8.9 0.8 1.1 4.00.5 103 (Y) 13.5 14.1 0.7 1.1 6.0 3.0 105 (X) 8.8 9.4 0.6 0.7 6.0 6.0106 (Y) 13.3 13.4 1.5 1.3 3.0 1.0 107 (Y) 5.2 5.7 0.3 0.8 3.0 0.5 108(X) 2.6 4.2 0.2 0.5 2.1 2.0 110 (X) 1.9 0.5 0.2 0.03 3.1 1.5 Mean ± SD9.5 ± 7.0 8.5 ± 4.7 0.9 ± 0.97 0.9 ± 0.44 3.8 ± 1.4 1.9 ± 1.9

Pharmacokinetic Profile

Pharmacokinetic (PK) analysis of the data generated from the above trialwas performed using the NONMEM (non-linear mixed effect modelling)program (GloboMax LLC, Hanover, Md., USA) to produce a pharmacokineticprofile. This models the absorption, elimination and distribution of adrug using different compartments. The pharmacological differencesbetween oral and intravenous administration are presented below.

Oral docetaxel exposure was examined following single doses of docetaxelalone and in combination with ritonavir. Ritonavir was administeredsimultaneously or one hour before oral docetaxel.

After drug administration blood samples were collected forpharmacokinetic analyses. A blank sample was taken before dosing. Bloodsamples were centrifuged, plasma was separated and immediately stored at−20° C. until analyses. Analysis were performed with validated HPLCmethods in a GLP (Good Laboratory Practice) licensed laboratory. Thisconcerns all pharmacokinetic studies presented here by the inventors.

PK Model

The PK model was based on the PK model of i.v. docetaxel. This modeluses three compartments and is well described by Bruno et al. [85]. Thedata generated from orally administered docetaxel were implementedwithin this model, adding an additional depot compartment modelling forthe gastrointestinal tract. The pharmacokinetic model for ritonavir wasbest described using a 2 compartment model, described by Kappelhoff et.al. [87]. FIG. 3 shows the final pharmacokinetic model schematically.The influence of ritonavir on the pharmacokinetics of docetaxel wasmodelled via two different mechanisms: a) improvement in the absorptionof docetaxel in the presence of ritonavir (line connecting ritonavir(RTV) compartments with absorption of docetaxel from C1 to C2); b)ritonavir inhibits active CYP3A4 (line connecting C6 with C7) and activeCYP3A4 is responsible for the elimination of docetaxel (line connectingC7 with the elimination route of docetaxel).

Absorption

Absorption of docetaxel markedly improved when co-administered withritonavir. The calculated bioavailability for oral docetaxel alone is14% (based on data of 3 patients who received 100 mg oral docetaxel).The bioavailability of oral docetaxel in combination with ritonavir was4 times higher at 56%. This effect can be credited to the inhibition ofCYP3A4 enzymes present in the GI tract by ritonavir.

Elimination

Docetaxel is primarily metabolised by CYP3A4. Ritonavir inhibits CYP3A4.This results in decreased elimination when ritonavir is co-administeredwith docetaxel. The clearance of docetaxel correlates with the amountCYP3A4 and thus varies over time. FIG. 4 shows the estimated relativeenzyme concentration over time. The clearance of docetaxel correlates1:1 with the enzyme concentration. Therefore, a graph of the clearanceof docetaxel versus time would be similar to FIG. 4.

Distribution Volume

The volume of the central compartment (C2 in FIG. 3) differs markedlybetween i.v. (+/−6 L) and oral (+/−60 L) administration. This isprobably due to polysorbate 80, one of the main excipients of thedocetaxel formulation. Polysorbate 80 forms micelles which are able toentrap docetaxel [86]. Polysorbate 80 enters the circulation in the caseof i.v. administration but is not absorbed in the case of oraladministration. Therefore, polysorbate does not affect thepharmacokinetic behaviour of docetaxel after oral administration due tothe fact that it is not absorbed.

Conclusions

Bioavailability of oral docetaxel increased approximately 4 times whenco-administered with ritonavir. Systemic exposure, in terms of AUC,increased 8.2 times, due to the combined effect of ritonavir on CYP3A4in the GI tract and the liver (i.e. absorption and elimination,respectively).

Elimination of docetaxel is decreased when combined with ritonavir.

The distribution volume (the volume of the central compartment) is smallin the presence of polysorbate 80 and large without polysorbate 80.

In the oral docetaxel studies mentioned above the commercially availablei.v. docetaxel formulation (Taxotere®; 2 ml=80 mg docetaxel; excipientpolysorbate 80) was diluted with ethanol 95%:water (13:87) to provide a10 mg/ml docetaxel solution. This solution, prepared by the pharmacist,was ingested orally by the patients (10 ml of the 10 mg/ml solution fora 100 mg dose) as a drinking solution combined with 100 ml of tap water.For investigational purposes this is feasible, however, it is not forroutine use and at home. Preparation of the drinking solution by thepharmacist is time-consuming. The solution has limited stability.Patients often complained of an unpalatable and unpleasant taste of thedrinking solution (probably due to polysorbate and ethanol excipients).Evidently, an oral solid dosage form (e.g. taken as capsule or tablet)is preferred and much more patient friendly.

In summary, the present invention improves the bioavailability andsystemic exposure of taxanes, improves the clinical efficacy of taxanes,especially oral taxanes, and probably also reduces the possible sideeffects associated with the treatment. This is economically andclinically beneficial.

EXAMPLE 3 Oral Formulations of Paclitaxel 3.1: Solid Dispersion VersusPhysical Mixture

In this experiment the solubility and dissolution rate of a compositioncomprising a solid dispersion of paclitaxel and PVP-K17 mixed with SDSwas compared to a physical mixture of anhydrous paclitaxel, PVP-K17 andSDS.

5 mg Capsules of Paclitaxel Solid Dispersions in PVP-K17

A solid dispersion of 20% paclitaxel in PVP-K17 was prepared bydissolving 100 mg of paclitaxel in 10 mL t-butanol and 400 mg PVP-K17 in6.67 mL water. The paclitaxel/t-butanol solution was added to thePVP-K17/water solution under constant stirring. The final mixture wastransferred to 8 mL vials with a maximum fill level of 2 mL. t-butanoland water were subsequently removed by lyophilisation (see table 3 forconditions). 25 mg of a paclitaxel 20%/PVP-K17 solid dispersion mgpaclitaxel) was mixed with 125 mg Lactose, 30 mg sodium dodecylsulphate, and 30 mg croscarmellose sodium. The resulting powder mixturewas encapsulated (see table 4).

TABLE 3 lyophilisation conditions: Lyovac GT4 (AMSCO/Finn-Aqua) Shelvetemperature Room pressure Maximum Step Time (hh:mm) (° C.) (%) pressure(%) 1 00:00 Ambient 100 100 2 01:00 −35 100 100 3 03:00 −35 100 100 403:01 −35 40 50 5 48:00 −35 40 50 6 63:00 25 40 50 7 66:00 25 40 50

TABLE 4 formulation of 5 mg paclitaxel/PVP-K17solid dispersion capsulesComponent Amount (mg) paclitaxel (inside the solid dispersion)  5 mgPVP-K17 (inside the solid dispersion) 20 mg Lactose monohydrate 125 mg sodium dodecyl sulphate 30 mg croscarmellose sodium 30 mg5 mg Capsules of Paclitaxel in a Physical Mixture with PVP-K17

A physical mixture was prepared by mixing 5 mg anhydrous paclitaxel with20 mg PVP, 125 mg lactose, 30 mg sodium dodecyl sulphate, and 30 mgcroscarmellose sodium. The resulting powder mixture was encapsulated.

TABLE 5 formulation of 5 mg paclitaxel/PVP-K17 physical mixture capsulesComponent Amount (mg) paclitaxel  5 mg PVP-K17 20 mg Lactose monohydrate125 mg  sodium dodecyl sulphate 30 mg croscarmellose sodium 30 mg

Dissolution Test

Both capsule formulations were tested in 900 mL of Water for Injectionmaintained at 37° C. in a USP 2 (paddle) dissolution apparatus with arotation speed of 75 rpm. In the first experiment, one capsule of eachformulation was used. In the second experiment, two capsules of eachformulation were used. Samples were collected at various timepoints andanalyzed by HPLC-UV (see table 4).

TABLE 6 chromatographic conditions Column Apex octyl 150 × 4.6 mm 5 μmEluens Methanol/Acetonitrile/0.02M Ammoniumacetate 1/4/5 v/v/v Flow 1.0mL/min Injection volume 50 μL Run time 15 minutes Detection wavelength227 nm

Results and Conclusions

The results are shown in FIG. 5. The amount of paclitaxel dissolved isexpressed relative to the label claim (5 and 10 mg). It can clearly beseen that the dissolution of paclitaxel is greatly improved by theincorporation in a solid dispersion with PVP. The maximum amount ofpaclitaxel dissolved stays below 20% relative to label claim when aphysical mixture is used. When a solid dispersion is used, thesolubility is about 65% (5 mg paclitaxel) or over 70% (10 mgpaclitaxel). For the 10 mg paclitaxel experiment, this corresponds to anabsolute solubility of about 8 μg/ml and this is achieved after about 15minutes. Therefore, the solid dispersion significantly increases thesolubility and also provides a rapid dissolution rate, both of which areimportant for bioavailability.

In a solid solution or solid dispersion, the amorphous state of thecarrier enables thorough mixing of the carrier and taxane. The carrierprevents crystallization during storage as well as during dissolution inaqueous media.

3.2: Addition of Sodium Dodecyl Sulphate to the Capsule Formulation

In this experiment, the effect on solubility of the presence or absenceof the surfactant SDS in the capsule was determined.

20% Paclitaxel Solid Dispersion in PVP-K17

A solid dispersion was prepared by dissolving 100 mg of Paclitaxel in 10mL t-butanol and 400 mg PVP-K17 in 6.67 mL water. Thepaclitaxel/t-butanol solution was added to the PVP-K17/water solutionunder constant stirring. The final mixture was transferred to 8 mL vialswith a maximum fill level of 2 mL. t-butanol and water were subsequentlyremoved by lyophilisation (see table 3).

5 mg Paclitaxel Capsules without Sodium Dodecyl Sulphate

25 mg of a paclitaxel 20%/PVP-K17 solid dispersion (=5 mg paclitaxel)was mixed with 125 mg Lactose and encapsulated (see table 7).

TABLE 7 formulation of 5 mg paclitaxel/PVP-K17 solid dispersion withoutsodium dodecyl sulphate capsules Component Amount (mg) paclitaxel(inside the solid dispersion)  5 mg PVP-K17 (inside the soliddispersion)  20 mg Lactose monohydrate 125 mg5 mg Paclitaxel Capsules with Sodium Dodecyl Sulphate

25 mg of a paclitaxel 20%/PVP-K17 solid dispersion (=5 mg paclitaxel)was mixed with 125 mg Lactose, 30 mg sodium dodecyl sulphate, and 30 mgcroscarmellose sodium. The resulting powder mixture was capsulated (seetable 8).

TABLE 8 formulation of 5 mg paclitaxel/PVP-K17 solid dispersion withsodium dodecyl sulphate capsules Component Amount (mg) paclitaxel(inside the solid dispersion)  5 mg PVP-K17 (inside the soliddispersion) 20 mg Lactose monohydrate 125 mg  sodium dodecyl sulphate 30mg croscarmellose sodium 30 mg

Dissolution Test

Both capsule formulations were tested in 900 mL of Water for Injectionmaintained at 37° C. in a USP 2 (paddle) dissolution apparatus with arotation speed of 75 rpm. Samples were collected at various timepointsand analyzed by HPLC-UV (see table 6).

Results and Conclusions

The results are shown in FIG. 6. The amount of paclitaxel dissolved isexpressed relative to the label claim (in this case 5 mg). The porosityof the lyophilized taxane and carrier solid dispersion was high enoughto ensure rapid dissolution when in powder form (results not shown).However, when the powder is compressed in capsules, the wettability isdramatically decreased. Therefore, a surfactant is needed to wet thesolid dispersion when it is compressed in capsules or tablets.

It can clearly be seen from FIG. 6 that the dissolution of paclitaxel isgreatly improved by the addition of the surfactant sodium dodecylsulphate. Previous experiments had shown that the addition ofcroscarmellose sodium, more lactose or the use of larger capsules didnot result in increased dissolution rates of the capsule formulation.Again, this shows that with a surfactant like SDS maximum dissolution isachieved in about 10-15 minutes.

3.3: Addition of Sodium Dodecyl Sulphate to the Solid DispersionFormulation

In this experiment, the effect on solubility of adding SDS to the soliddispersion was determined.

Paclitaxel 40% Solid Dispersion in PVP-K17

A solid dispersion was prepared by dissolving 600 mg of Paclitaxel in 60mL t-butanol and 900 mg PVP-K17 in 40 mL water. The paclitaxel/t-butanolsolution was added to the PVP-K17/water solution under constantstirring. The final mixture was transferred to 8 mL vials with a maximumfill level of 2 mL. t-butanol and water were subsequently removed bylyophilisation (see table 3).

Paclitaxel 40% Solid Dispersion in PVP-K17 and Sodium Dodecyl Sulphate10%

A solid dispersion was prepared by dissolving 250 mg of Paclitaxel in 25mL t-Butanol, and 375 mg PVP-K17 and 62.5 mg sodium dodecyl sulphate(SDS) in 16.67 mL water. The paclitaxel/t-butanol solution was added tothe PVP-K17/sodium dodecyl sulphate/water solution under constantstirring. The final mixture was transferred to 8 mL vials with a maximumfill level of 2 mL. t-butanol and water were subsequently removed bylyophilisation (see table 3).

25 mg Paclitaxel Capsules of Paclitaxel/PVP-K17 Solid Dispersion

62.5 mg of a paclitaxel 40%/PVP-K17 solid dispersion (=25 mg paclitaxel)was mixed with 160 mg lactose, 30 mg sodium dodecyl sulphate and 10 mgcroscarmellose sodium. The resulting powder mixture was encapsulated(see table 9).

TABLE 9 formulation of 25 mg paclitaxel/PVP-K17 solid dispersioncapsules Component Amount (mg) paclitaxel (inside the solid dispersion)25 mg PVP-K17 (inside the solid dispersion) 37.5 mg   Lactosemonohydrate 125 mg  sodium dodecyl sulphate 30 mg croscarmellose sodium10 mg

25 mg Paclitaxel Capsules of Paclitaxel/PVP-K17/Sodium Dodecyl SulphateSolid Dispersion

68.75 mg of a paclitaxel 40%/PVP-K17/sodium dodecyl sulphate 10% soliddispersion (=25 mg paclitaxel) was mixed with 160 mg lactose and 10 mgcroscarmellose sodium. The resulting powder mixture was encapsulated(see table 10).

TABLE 10 formulation of 25 mg paclitaxel/PVP-K17 solid dispersioncapsules Component Amount (mg) paclitaxel (inside the solid dispersion)  25 mg PVP-K17 (inside the solid dispersion) 37.5 mg sodium dodecylsulphate (inside the solid dispersion) 6.25 mg Lactose monohydrate  125mg croscarmellose sodium   10 mg

Dissolution Test

Both capsule formulations were tested in 500 mL of Water for Injectionmaintained at 37° C. in a USP 2 (paddle) dissolution apparatus. Rotationspeed was set at 75 rpm for the capsule with paclitaxel/PVP-K17/sodiumdodecyl sulphate solid dispersion and at 100 rpm for the capsule withpaclitaxel/PVP-K17 solid dispersion. Samples were collected at varioustimepoints and analyzed by HPLC-UV (see table 6).

Results and Conclusions

The results are shown in FIG. 7. The amount of paclitaxel dissolved isexpressed relative to the label claim (in this case 25 mg). It canclearly be seen that the dissolution of paclitaxel from capsules withsodium dodecyl sulphate incorporated in the solid dispersion iscomparable to the dissolution of paclitaxel from capsules with sodiumdodecyl sulphate added to the capsule. Furthermore only 6.25 mg sodiumdodecyl sulphate was used for incorporation into the solid dispersion,while 30 mg sodium dodecyl sulphate was used as addition to the capsuleformulation. This shows that less surfactant is required when it isincorporated into the solid dispersion rather than into the capsule inorder to achieve the similar results. Another surprising result fromthis experiment is that both compositions provide an absolute paclitaxelsolubility of about 26 μg/ml and this level is reached in 20-30 minutes.This result provides a higher solubility and faster dissolution ratethan has previously been achieved.

3.4: Influence of Carrier

The solid dispersions used in the experiments of example 3.4 wereproduced after initial experiments did not show clear differencesbetween drugloads. The 40% drugload was selected because theseformulations performed equally to 20% drugload formulation in the aforementioned experiments and offered the possibility to deliver more taxanein one tablet or capsule.

Paclitaxel 40% Solid Dispersion in PVP-K12

A solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25mL t-butanol and 375 mg PVP-K12 in 16.67 mL water. Thepaclitaxel/t-butanol solution was added to the PVP-K12 water solutionunder constant stirring. The final mixture was transferred to 8 mL vialswith a maximum fill level of 2 mL. t-butanol and water were subsequentlyremoved by lyophilisation (see table 3).

Paclitaxel 40% Solid Dispersion in PVP-K17

A solid dispersion was prepared by dissolving 600 mg of paclitaxel in 60mL t-butanol and 900 mg PVP-K17 in 40 mL water. The paclitaxel/t-butanolsolution was added to the PVP-K17 water solution under constantstirring. The final mixture was transferred to 8 mL vials with a maximumfill level of 2 mL. t-butanol and water were subsequently removed bylyophilisation (see table 3).

Paclitaxel 40% Solid Dispersion in PVP-K30

A solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25mL t-Butanol and 375 mg PVP-K30 in 16.67 mL water. Thepaclitaxel/t-butanol solution was added to the PVP-K30 water solutionunder constant stirring. The final mixture was transferred to 8 mL vialswith a maximum fill level of 2 mL. t-butanol and water were subsequentlyremoved by lyophilisation (see table 3).

Paclitaxel 40% Solid Dispersion in HP-Cyclodextrin

A solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25mL t-butanol and 375 mg HP-cyclodextrin in 16.67 mL water. Thepaclitaxel/t-butanol solution was added to the HP-cyclodextrin watersolution under constant stirring. The final mixture was transferred to 8mL vials with a maximum fill level of 2 mL. t-butanol and water weresubsequently removed by lyophilisation (see table 3).

25 mg Paclitaxel Solid Dispersion Capsules

62.5 mg of the paclitaxel/carrier solid dispersion (=25 mg paclitaxel)was mixed with 160 mg Lactose, 30 mg sodium dodecyl sulphate and 10 mgcroscarmellose sodium. The resulting powder mixture was encapsulated(see table 11).

TABLE 11 formulation of 25 mg paclitaxel/carrier solid dispersioncapsules Component Amount (mg) paclitaxel (inside the solid dispersion)25 mg carrier (inside the solid dispersion) 37.5 mg   Lactosemonohydrate 125 mg  sodium dodecyl sulphate 30 mg croscarmellose sodium10 mg

Dissolution Test

All capsule formulations were tested in 500 mL of Water for Injectionmaintained at 37° C. in a USP 2 (paddle) dissolution apparatus with arotation speed of 100 rpm. Samples were collected at various timepointsand analyzed by HPLC-UV (see table 6).

Results and Conclusions

The average results of 2 to 3 experiments are shown in FIG. 8. Theamount of paclitaxel dissolved is expressed relative to the label claim(in this case 25 mg). It can clearly be seen that the dissolution ofpaclitaxel from the PVP-K30 solid dispersion is as fast as thedissolution of paclitaxel from the PVP-K17 solid dispersion. However,the amount of paclitaxel dissolved remains higher throughout the 4 hourexperiment in the case of the PVP-K30 solid dispersion.

The chain length of the polymeric carrier determines the time tocrystallization in aqueous environments.

3.5: Influence of Drug/Carrier Ratio

The solid dispersions used in the experiments of example 3.5 wereproduced after initial experiments did not show clear differencesbetween carriers. These initial experiments were done before the moredetailed experiments of Example 3.4. As a result, PVP-K17 wasarbitrarily chosen as carrier for further experiments.

Paclitaxel 10% Solid Dispersion in PVP-K17

A solid dispersion was prepared by dissolving 100 mg of paclitaxel in 10mL t-butanol and 900 mg PVP-K17 in 40 mL water. The paclitaxel/t-butanolsolution was added to the PVP-K17 water solution under constantstirring. The final mixture was transferred to 8 mL vials with a maximumfill level of 2 mL. t-butanol and water were subsequently removed bylyophilisation (see table 3).

Paclitaxel 25% Solid Dispersion in PVP-K17

A solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25mL t-butanol and 750 mg PVP-K17 in 16.67 mL water. Thepaclitaxel/t-butanol solution was added to the PVP-K17 water solutionunder constant stirring. The final mixture was transferred to 8 mL vialswith a maximum fill level of 2 mL. t-butanol and water were subsequentlyremoved by lyophilisation (see table 3).

Paclitaxel 40% Solid Dispersion in PVP-K17

A solid dispersion was prepared by dissolving 600 mg of paclitaxel in 60mL t-butanol and 900 mg PVP-K17 in 6.67 mL water. Thepaclitaxel/t-butanol solution was added to the PVP-K17 water solutionunder constant stirring. The final mixture was transferred to 8 mL vialswith a maximum fill level of 2 mL. t-butanol and water were subsequentlyremoved by lyophilisation (see table 3).

Paclitaxel 75% Solid Dispersion in PVP-K17

A solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25mL t-butanol and 83 mg PVP-K17 in 16.67 mL water. Thepaclitaxel/t-butanol solution was added to the PVP-K17 water solutionunder constant stirring. The final mixture was transferred to 8 mL vialswith a maximum fill level of 2 mL. t-butanol and water were subsequentlyremoved by lyophilisation (see table 3).

Paclitaxel 100% Solid Dispersion

A solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25mL t-butanol. The paclitaxel/t-butanol solution was added to 16.67 mLwater under constant stirring. The final mixture was transferred to 8 mLvials with a maximum fill level of 2 mL. t-butanol and water weresubsequently removed by lyophilisation (see table 3).

Dissolution Test

An amount of solid dispersion powder, equal to approximately 4 mgPaclitaxel, was placed in a 50 mL beaker. A magnetic stirring bar and 25mL water was added to the beaker. The solution was stirred at 7200 rpm.Samples were collected at various timepoints and analyzed by HPLC-UV(see table 6).

Results and Conclusions

The average results of 2 to 3 experiments are shown in FIG. 9. Theamount of paclitaxel (PCT) dissolved is expressed relative to the labelclaim (in this case approximately 4 mg). The influence of thedrug/carrier ratio is immediately apparent from FIG. 9. The value of thepeak concentration of paclitaxel inversely related to the drug/carrierratio. The highest peak concentration is reached with the lowestdrug/carrier ratio (10%), while the lowest peak concentration is reachedwith the highest drug/carrier ratio (100%). Furthermore, the AUC-valuesof the 10% drug/carrier ratio solid dispersion are the highest, followedby the AUC-values of 25, 40, 75 and 100% drug/carrier ratio soliddispersions.

The amount of carrier relative to the amount of drug determines the timeto crystallization in aqueous environments.

3.6: Influence of Enteric Coating Paclitaxel 40% Solid Dispersion inPVP-K17 and Sodium Dodecyl Sulphate 10%

A solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25mL t-butanol, and 375 mg PVP-K17 and 62.5 mg sodium dodecyl sulphate(SDS) in 16.67 mL water. The paclitaxel/t-butanol solution was added tothe PVP-K17/sodium dodecyl sulphate/water solution under constantstirring. The final mixture was transferred to 8 mL vials with a maximumfill level of 2 mL. t-butanol and water were subsequently removed bylyophilisation (see table 3).

25 mg Paclitaxel Capsules of Paclitaxel/PVP-k17/Sodium Dodecyl SulphateSolid Dispersion

68.75 mg of a paclitaxel 20%/PVP-K17/sodium dodecyl sulphate 10% soliddispersion (=25 mg paclitaxel) was mixed with 160 mg lactose and 10 mgcroscarmellose sodium. The resulting powder mixture was encapsulated(see table 12).

TABLE 12 formulation of 25 mg paclitaxel/PVP-K17/SDS solid dispersioncapsules Component Amount (mg) paclitaxel (inside the solid dispersion)  25 mg PVP-K17 (inside the solid dispersion) 37.5 mg sodium dodecylsulphate (inside the solid dispersion) 6.25 mg Lactose monohydrate  125mg croscarmellose sodium   10 mg

Dissolution Test

The capsules were in duplo subjected to two different dissolution tests.The first test was a two tiered dissolution test, consisting of twohours of dissolution testing in 500 mL simulated gastric fluid withoutpepsin (SGF_(sp); see table 13) followed by two hours of dissolutiontesting in 629 mL simulated intestinal fluid without pepsin (SIF_(sp);see table 13). The second test was conducted in 500 mL fasted statesimulated intestinal fluid (FaSSIF; see table 14) medium for four hours.

Both dissolution tests were performed in a USP 2 (paddle) dissolutionapparatus with 500 mL medium maintained at 37° C. and paddle rotationspeed 75 rpm. The SGFsp medium was changed to SIFsp medium by additionof 129 mL switch medium. Samples were collected at various timepointsand analyzed by HPLC-UV (see table 6).

TABLE 13 SGF_(sp), SIF_(sp) and switch medium [96] Medium VolumeComponents SGF_(sp) (USP 26) 500 mL 1.0 g NaCL, 3.5 mL HCl, q.s. 500 mLWater for Injection Switch medium 129 mL 4.08 g KH₂PO4, 30 mL NaOHsolution 80 g/L (2.0M), 129 mL Water for Injection SIF_(sp) + NaCL 629ML 500 mL SGF_(sp) and 129 mL switch medium (USP 24)

TABLE 14 Fasted state simulated intestinal fluid (FaSSIF) medium [97]Component Amount KH₂PO4 3.9 g NaOH q.s. pH 6.5 Na taurocholate 3 mMLecithin 0.75 mM KCl 7.7 g Distilled water q.s. 1 L

Results and Conclusions

The results are shown in FIG. 10. The amount of paclitaxel dissolved isexpressed relative to the label claim (in this case 25 mg). Paclitaxeldissolution in Fasted state simulated intestinal fluid is approximately20% higher than in simulated gastric fluid (SGFsp). After two hours inSGFsp the amount of paclitaxel in solution is only slightly increasedwhen the medium is changed to simulated intestinal fluid (SIFsp).

An enteric coating will prevent release of the taxane in the stomach,thereby preventing degradation of the active components. Furthermore, itwill enable targeted delivery to the intestines where the taxane isabsorbed, thus ensuring that the limited time the taxane is present insolution (before crystallization takes place), is only spent at siteswhere absorption is possible.

EXAMPLE 4 Oral Formulations of Docetaxel Materials and Methods

The formulations used in the following experiments were preparedaccording to the procedures outline below and the compositions depictedin table 15.

Pure Anhydrous Docetaxel

Anhydrous docetaxel was used as obtained from ScinoPharm, Taiwan.

Pure Amorphous Docetaxel

Docetaxel was amorphized by dissolving 300 mg of Docetaxel anhydrate in30 mL of t-butanol. The docetaxel/t-butanol solution was added to 20 mLof Water for Injection (WfI) under constant stirring. The final mixturewas transferred to a stainless steel lyophilisation box (Gastronorm size1/9), t-butanol and water were subsequently removed by lyophilisation(see table 16).

Physical Mixtures

Physical mixtures were prepared by mixing 150 mg of docetaxel andcorresponding amounts of carrier and surfactant (see table 15) withmortar and pestle.

Solid Dispersions

Solid dispersions were obtained by dissolving 300 mg docetaxel anhydratein 30 mL of t-butanol, and corresponding amounts of carrier andsurfactant (see table 15) in 20 mL of Water for Injection. Thedocetaxel/t-butanol solution was added to the carrier/surfactant/WfIsolution under constant stirring. The final mixture was transferred to astainless steel lyophilisation box (Gastronorm size 1/9), t-butanol andwater were subsequently removed by lyophilisation (see table 16).

TABLE 15 Composition of the tested formulations Formu- Amount AmountSurfac- Amount lation Type Drug Part (mg) Carrier Part (mg) tant (mg)Part A Pure Anhydrous 1 150 — — — — drug Docetaxel B Pure Amorphous 1450 — — — — drug Docetaxel C Physical Anhydrous  1/11 150 PVP-  9/111350 SDS 150  1/11 mixture Docetaxel K30 D Physical Amorphous  1/11 150PVP-  9/11 1350 SDS 150  1/11 mixture Docetaxel K30 E Solid Amorphous 1/11 300 PVP-  9/11 2700 SDS 300  1/11 dispersion Docetaxel K30 F SolidAmorphous  1/11 300 HPβ-  9/11 2700 SDS 300  1/11 dispersion DocetaxelCD¹ G Solid Amorphous  1/11 300 PVP-  9/11 2700 SDS 300  1/11 dispersionDocetaxel K12 H Solid Amorphous  1/11 300 PVP-  9/11 2700 SDS 300  1/11dispersion Docetaxel K17 I Solid Amorphous  1/11 300 PVP-  9/11 2700 SDS300  1/11 dispersion Docetaxel K25 J Solid Amorphous  1/11 300 PVP- 9/11 2700 SDS 300  1/11 dispersion Docetaxel K90 K Solid Amorphous 5/7300 PVP-  5/21  100 SDS  20  1/21 dispersion Docetaxel K30 L SolidAmorphous 1/3 300 PVP- 1/2  450 SDS 150 1/6 dispersion Docetaxel K30 MSolid Amorphous 1/6 300 PVP- 2/3 1200 SDS 300 1/6 dispersion DocetaxelK30 N Solid Amorphous  1/21 300 PVP- 19/21 5700 SDS 300  1/21 dispersionDocetaxel K30 ¹HPβ-CD is hydroxypropyl-β-cyclodextrin

TABLE 16 lyophilisation conditions Shelve temperature Room pressureMaximum Step Time (hh:mm) (° C.) (mbar) pressure (mbar) 1 00:00 Ambient1000 1000 2 01:00 −35 1000 1000 3 03:00 −35 1000 1000 4 03:01 −35 0.20.6 5 48:00 −35 0.2 0.6 6 63:00 25 0.2 0.6 7 66:00 25 0.2 0.6

Dissolution Test

An amount of powder, equal to approximately 6 mg Docetaxel, was placedin a 50 mL beaker. A magnetic stirring bar and 25 mL water were added tothe beaker. The solution was stirred at 720 rpm, and kept atapproximately 37° C. Samples were collected at various timepoints, andfiltrated using a 0.45 μm filter before they were diluted with a 1:4 v/vmixture of methanol and acetonitrile. The filtrated and diluted sampleswere subsequently analyzed by HPLC-UV (see table 17).

TABLE 17 chromatographic conditions Column Apex octyl 150 × 4.6 mm 5 μmEluens Methanol/Acetonitrile/0.02M Ammoniumacetate 1/4/5 v/v/v Flow 1.0mL/min Injection volume 10 μL Run time 20 minutes Detection wavelength227 nm

4.1: Formulation Type

In the first experiment, the influence of the formulation type on thesolubility of docetaxel was examined. Data from the dissolution testperformed on formulations A to E were compared. The results are shown inFIG. 11. Formulation E was tested in quadruplicate, formulation A to Dwere tested in duplicate.

Results

Formulation A (pure docetaxel anhydrate) reaches a maximum concentrationof approximately 12 μg/mL (4.7% total docetaxel present) after 5 minutesof stirring and reaches an equilibrium concentration of approximately 6μg/mL (2%) after 15 minutes of stirring.

Formulation B (pure amorphous docetaxel) reaches a maximum of 32 μg/mL(13%) after 0.5 minutes, from 10 to 60 minutes the solubility iscomparable to formulation A.

Formulation C (physical mixture of anhydrous docetaxel, PVP-K30 and SDS)reaches a concentration of approximately 85 μg/mL (37%) after 5 minutes.Between 15 and 25 minutes, the docetaxel concentration sharply declinesfrom 85 μg/mL (37%) to 30 μg/mL (12%), after which it further declinesto 20 μg/mL (9%) at 60 minutes.

Formulation D (physical mixture of amorphous docetaxel, PVP-K30 and SDS)reaches a maximum docetaxel concentration of 172 μg/mL (70%) after 7.5minutes. Between 7.5 and 20 minutes, the amount of docetaxel in solutiondrops to 24 μg/mL (10%). At 60 minutes, the equilibrium concentration of19 μg/mL (7%) is reached.

Formulation E (solid dispersion of amorphous docetaxel, PVP-K30 and SDS)has the highest maximum concentration of 213 μg/mL (90%) which isreached after 5 minutes. Between 10 and 25 minutes, the amount ofdocetaxel in solution rapidly declines resulting in an equilibriumconcentration of 20 μg/mL (8%) after 45 minutes.

Conclusions

All formulations initially show a higher solubility, which decreases toan equilibrium solubility after 45 to 60 minutes of stirring. Thedecrease in solubility is caused by the crystallization of docetaxel asa result of the supersaturated solution. The degree of supersaturationis dependent on the physical state of the drug, i.e. whether it isamorphous or crystalline. When PVP-K30 is the carrier, thesupersaturated state is maintained for longer so that the solubility ofthe docetaxel does not decrease as quickly. Further, the results showthat using amorphous docetaxel significantly increases the solubility ofdocetaxel compared to anhydrous docetaxel. Further, amorphous docetaxelshows a relatively high dissolution rate, peaking at about 5 to 7.5minutes.

This experiment shows that the amount of docetaxel in solution ismarkedly increased by physical mixing of anhydrous docetaxel withPVP-K30 and SDS, and even more by physical mixing of amorphous docetaxelwith PVP-K30 and SDS. The biggest increase in solubility however isachieved by incorporation of docetaxel in a solid dispersion of PVP-K30and SDS.

4.2: Carrier Type

In the second experiment, the influence of the carrier type on thesolubility of docetaxel was examined. Data from the dissolution testperformed on formulation E and F were compared. The results are shown inFIG. 12. Formulation E was tested in quadruplicate, formulation F wastested in duplicate.

Results

Formulation E (solid dispersion of amorphous docetaxel, PVP-K30 and SDS)has a highest maximum concentration of 213 μg/mL (90% of total docetaxelpresent) which is reached after 5 minutes. Between 10 and 25 minutes,the amount of docetaxel in solution rapidly declines, resulting in anequilibrium concentration of 20 μg/mL (8%) after 45 minutes.

Formulation F (solid dispersion of amorphous docetaxel, HPβ-CD and SDS)reaches a maximum docetaxel concentration of approximately 200 μg/mL(81%) after about 2 minutes. Between 5 and 10 minutes, the amount ofdocetaxel in solution drops to a value of 16 μg/mL (6%) and after 45minutes, an equilibrium concentration of 11 μg/mL (4%) is reached.

Conclusions

This experiment shows that both PVP-K30 and HPβ-CD increase thesolubility of docetaxel. When PVP-K30 is used as the carrier compared toHPβ-CD, the maximum docetaxel concentration is slightly higher and thestate of supersaturation is maintained longer so that the solubility ofdocetaxel does not decrease as quickly with time. Further, theequilibrium concentration reached after precipitation of docetaxel ishigher with PVP-K30 compared to HPβ-CD.

4.3: Chain Length

In the third experiment, the influence of the PVP chain length on thesolubility of docetaxel was examined. Data of the dissolution testperformed on formulation E and G to J were compared. The results areshown in FIG. 13. Formulation E was tested in quadruplicate, formulationG to J were tested in duplicate.

Results

Formulation G (PVP-K12) reaches a maximum docetaxel concentration of 206μg/mL (77% of the total docetaxel present) after 5 minutes. Between 5and 30 minutes, the amount of docetaxel in solution decreases to 20μg/mL (7%) and at 45 minutes, the docetaxel concentration is 17 μg/mL(6%).

Formulation H (PVP-K17) reaches a maximum docetaxel concentration of 200μg/mL (83%) after 5 minutes and maintains this concentration up to 10minutes of stirring, after which the amount of docetaxel in solutionrapidly drops to 44 μg/mL (18%) at 15 minutes and 22 μg/mL (9%) at 30minutes. The equilibrium concentration between 45 and 60 minutes isapproximately 21 μg/mL (8%).

Formulation I (PVP-K25) reaches a maximum docetaxel concentration of 214μg/mL (88%) after 5 minutes of stirring. The amount of docetaxel insolution decreases between 10 and 30 minutes to 22 μg/mL (9%) and at 60minutes, the concentration of docetaxel is 19 μg/mL (8%).

Formulation E (PVP-K30) has a maximum docetaxel concentration of 213μg/mL (90%) which is reached after 5 minutes. Between 10 and 25 minutes,the amount of docetaxel in solution rapidly declines, resulting in anequilibrium concentration of 20 μg/mL (8%) after 45 minutes.

Formulation J (PVP-K90) reaches a maximum docetaxel concentration of 214μg/mL (88%) after 10 minutes of stirring. At 15 minutes, the amount ofdocetaxel in solution is still 151 μg/mL (61%). After 60 minutes, thedocetaxel concentration has declined to 19 μg/mL (7%).

Conclusions

This experiment shows that the chain length of PVP influences both thedegree of supersaturation and the period the supersaturation ismaintained. The use of higher PVP chain lengths results in a highermaximum docetaxel concentrations and a longer period of supersaturation,thus, a higher solubility for a longer period of time.

4.4: Drug load

In the fourth experiment, the influence of the drug load on thesolubility of docetaxel was examined. Data from the dissolution testsperformed on formulations E and K to N were compared. The results areshown in FIG. 14. Formulation E was tested in quadruplicate, formulationK to N were tested in duplicate.

Formulation N (1/21 docetaxel by weight of total composition; 5:95 w/wdocetaxel to PVP) reaches a maximum docetaxel concentration of 197 μg/mL(79% of total docetaxel present) after 10 minutes. After 15 minutes, theamount of docetaxel in solution is still 120 μg/mL (48%) and between 15and 30 minutes, the docetaxel concentration decreases to 24 μg/mL (12%).At 60 minutes the docetaxel concentration is 20 μg/mL (8%).

Formulation E (1/11 docetaxel by weight of total composition; 10:90 w/wdocetaxel to PVP) has a maximum concentration of 213 μg/mL (90%) whichis reached after 5 minutes. Between 10 and 30 minutes, the amount ofdocetaxel in solution rapidly declines and reaches an equilibriumconcentration of 20 μg/mL (8%) after 45 minutes.

Formulation M (1/6 docetaxel by weight of total composition; 20:80 w/wdocetaxel to PVP) has a docetaxel concentration of 196 μg/mL (80%) after10 minutes of stirring. The amount of docetaxel in solution decreasesbetween 10 and 30 minutes to 25 μg/mL (10%) and at 60 minutes, theconcentration of docetaxel is 18 μg/mL (7%).

Formulation L (1/3 docetaxel by weight of total composition; 40:60 w/wdocetaxel to PVP) reaches a docetaxel concentration of 176 μg/mL (71%).Between 10 and 15 minutes, the amount of docetaxel in solution rapidlydrops to 46 μg/mL (18%) and after 60 minutes, the amount of docetaxel insolution is 18 μg/mL (7%).

Formulation K (5/7 docetaxel by weight of total composition; 75:25 w/wdocetaxel to PVP) reaches a maximum docetaxel value of 172 μg/mL (71%)after 5 minutes of stirring. Between 5 and 10 minutes, the docetaxelconcentration sharply declines to 42 μg/mL (17%) and after 60 minutes, adocetaxel concentration of 18 μg/mL (7%) is reached.

Conclusions

This experiment shows that the amount of PVP-K30 relative to the amountof docetaxel used in the solid dispersions influences both the degree ofsupersaturation and the period the supersaturation is maintained. Theuse of higher drugloads results in lower maximum docetaxelconcentrations and a shorter period of supersaturation, thus, a lowersolubility over time.

4.5: Solubility Comparison with a Prior Art Composition

In this experiment, a composition containing a solid dispersion of 15 mgdocetaxel, 135 mg PVP-K30 and 15 mg SDS was compared to a the literaturedata of a composition comprising a solid dispersion of 5 mg docetaxeland PVP-K30 as disclosed in Chen et al. [95]. The solubility resultswere obtained using the dissolution test described in Chen et al. [95]and are shown in FIGS. 15 and 16. A dissolution test was also conductedin Simulated Intestinal Fluid and compared to the literature data ofChen. The results are shown in FIG. 17.

Results

From FIG. 15, it can be seen that the composition of Chen et al. candissolve a maximum of about 80% of the 5 mg docetaxel in the compositionin 900 ml water. It took over 5 hours to reach this maximum. Thedocetaxel, PVP-K30 and SDS composition dissolved 100% of the 15 mgdocetaxel in about 60 minutes.

In FIG. 16, the absolute concentration of docetaxel is given. Thecomposition of Chen gave a maximum docetaxel concentration of about 4.2μg/ml after about 5 hours. The docetaxel, PVP-K30 and SDS compositiongave a maximum docetaxel concentration of about 16.7 μg/ml after about60 minutes.

In FIG. 17, the docetaxel capsules reach a solubility of 28 μg/ml (>90%solubility). The solid dispersion described by Chen et al.(docetaxel+PVP K30) reaches a solubility of 4.2 μg/ml (lower than 80% ofthe 5 mg docetaxel solid dispersion tested for dissolution in 900 ml).The capsule formulation thus reaches a 6.6 fold better solubility with ahigher dissolution rate (maximum reached after 30 minutes versus 90-120minutes by Chen).

Conclusions

From these results, it can be seen that the docetaxel, PVP-K30 and SDScomposition gave a faster dissolution rate and a higher solubilitycompared to the composition of Chen. For bioavailability, it isimportant to look at how fast a drug dissolves and what solubility isreached in 0.5 to 1.5 h.

From the results of Chen, a skilled person would not consider thatincreasing the amount of docetaxel in the composition would increase theabsolute solubility of docetaxel. Since the composition of Chendissolves only 80% of 5 mg docetaxel (i.e. 4 mg) in 900 ml water, youwould not expect that increasing the amount of docetaxel to 15 mg wouldcause any more than 4 mg docetaxel to dissolve. Thus, you would expect a15 mg docetaxel composition according to Chen to dissolve a maximum ofabout 27% docetaxel compared to 100% for the docetaxel, PVP-K30 and SDScomposition. Therefore, the docetaxel, PVP-K30 and SDS compositionprovides surprisingly good results compared to Chen.

4.6: Dissolution Test in Simulated Intestinal Fluid Sine Pancreatin(SIFsp)

In this experiment, the dissolution of capsules, containing a soliddispersion of docetaxel, PVP-K30 and SDS, was tested in SimulatedIntestinal Fluid sine Pancreatin (SIFsp). The capsules contained 15 mgdocetaxel according to Formulation E (see table 15). SIFsp was preparedaccording to USP 28. Capsules containing 15 mg docetaxel were dissolvedin 500 mL USP SIFsp at 37° C. with stirring at 75 rpm. The results areshown in FIGS. 18 and 19.

FIGS. 18 and 19 show that nearly 100% of the docetaxel dissolved. Thisis equivalent to an absolute docetaxel concentration of about 29 μg/mland is achieved in about 30 minutes. Thus, the composition provides arelatively high solubility in a relatively short period of time.

4.7: Stability

It was found that the solid dispersion of docetaxel, PVP-K30 and SDSaccording to Formulation E (see table 15) and which was used in capsulesfor clinical trials (see following Example) is stable both chemically(no degradation) and physically (no changes in solubilitycharacteristics) for at least 80 days when stored between 4-8° C.

EXAMPLE 5 Clinical Trial Data with Formulations Materials and Methods

10 patients participated in an ongoing clinical phase I trial.

These patients were given the following numbers:

301, 302, 303, 304, 305, 306, 307, 308, 309 and 310.

These patients were given medication which consisted of a liquidformulation of docetaxel or a solid composition comprising a soliddispersion of docetaxel, PVP-K30 and SDS (referred to hereinafter asMODRA).

Liquid Formulation

Docetaxel dose: 30 mg for all patients (with the exception of patient306 who received 20 mg docetaxel). The 30 mg dose was prepared asfollows: 3.0 mL Taxotere® premix for intravenous administration(containing 10 mg docetaxel per ml in polysorbate 80 (25% v/v), ethanol(10% (w/w), and water) was mixed with water to a final volume of 25 mL.This solution was orally ingested by the patient with 100 mL tap water.

MODRA

Docetaxel dose: 30 mg; 2 capsules with 15 mg docetaxel per capsule wereingested. Formulation E from the previous example (1/11 docetaxel, 9/11PVP-K30 and 1/11 SDS) was selected for further testing in the clinicaltrial. A new batch of formulation E was produced by dissolving 1200 mgdocetaxel anhydrate in 120 mL of t-butanol, and 10800 mg PVP-K30 and1200 mg SDS (see table 15) in 80 mL of Water for Injection. Thedocetaxel/t-butanol solution was added to the PVP-K30/SDS/WfI solutionunder constant stirring. The final mixture was transferred to astainless steel lyophilisation box (Gastronorm size 1/3), t-butanol andwater were subsequently removed by lyophilisation (see table 16).

A total of 60 gelatine capsules of size 0 were filled with an amount ofsolid dispersion equivalent to 15 mg docetaxel, an HPLC assay was usedto determine the exact amount of docetaxel per mg of solid dispersion.The assay confirmed that the capsules contained 15 mg docetaxel.

Patients took the medication orally on an empty stomach in the morningwith 100 mL tap water.

Patient Treatment

Patients 301, 302, 303, 304 and 305 received only liquid formulation.

Patient 306 received 20 mg docetaxel as liquid formulation+ritonavir inthe first cycle and in the second cycle the same medication but withextra ritonavir 4 hours after docetaxel ingestion.

Patients 307, 308, 309 and 310 received liquid formulation and/or MODRA.Cycles were administered in a weekly interval.

According to institutional guidelines, for both oral and i.v. docetaxelall patients were treated with oral dexamethason. A dose of 4 mgdexamethason was given 1 hour prior to the study drugs, followed by 4 mgevery 12 hours (2 times). One hour prior to docetaxel treatment,patients also received 1 mg granisetron (Kytril®) to prevent nausea andvomiting.

After drug administration, blood samples were collected forpharmacokinetic analyses. A blank sample was taken before dosing. Bloodsamples were centrifuged, plasma was separated and immediately stored at−20° C. until analyses. Analysis were performed with validated HPLCmethods in a GLP (Good Laboratory Practice) certified laboratory [101].

Results

Table 18 gives an overview of the individual pharmacokinetic results.

Conc AUC AUC ID Treatment Cycle Tlast (h) l last last inf 20mgdocLF 1x306 RTV 1 48.03 0.668 242.7 256.5 20mgdocLF 2x 306 RTV 2 48.02 1.34357.2 384.5 301 30 mg docLF 2 47.78 1.42 556.7 586.5 302 30 mg docLF 28.15 141 2227.1 3028.1 303 30 mg docLF 2 48 3.28 663.9 745.4 304 30 mgdocLF 2 47.77 2.67 723.4 761.3 305 30 mg docLF 2 48.07 0.498 129.8 140.5307 30 mg docLF 3 23.9 5.17 754.3 822.0 309 30 mg docLF 1 24.02 14.12127.5 2327.0 310 30 mg docLF 1 24.17 6.17 758.7 836.1 307 MODRA 30 mg 124.07 4.23 420.8 473.8 307 MODRA 30 mg 2 23.97 7.05 782.1 873.6 308MODRA 30 mg 1 23.95 10.9 645.7 879.2 308 MODRA 30 mg 2 24.02 7.76 507.3625.9 309 MODRA 30 mg 2 23.8 7.09 892.2 994.1 310 MODRA 30 mg 2 23.638.52 650.7 760.3 docLF: docetaxel liquid formulation MODRA: docetaxelcapsule formulation Tlast: time at which last sample for measurementdocetaxel concentration was taken (in h) Conc last: docetaxelconcentration at Tlast (in ng/mL) AUC last: AUC calculated until Conclast (ng · h/mL) AUC inf: AUClast + extrapolation to infinity (ng ·h/mL) Ritonavir dosage is in all cases 100 mg (capsule, Norvir ®)

Patients 301, 302, 303, 304, 305, 307, 309 and 310 received the liquidformulation.

The mean, and the 95% confidence interval for the mean of the AUC(extrapolated to infinity) is: 1156 (±348) ng*h/mL. The inter-individualvariability is 85%.

Patient 306 received 20 mg docetaxel (as liquid formulation)concomitantly with 100 mg ritonavir in the first cycle and the samecombination, one week later, in the second cycle but with 100 mg extraritonavir 4 hours after ingestion of docetaxel, i.e. two doses ofritonavir were taken, one at t=0 and the second at t=4 h. Thepharmacokinetic curves are depicted in FIG. 20.

Patients 307, 308, 309 and 310 received liquid formulation and/or MODRA.The pharmacokinetic curves are depicted in FIG. 21.

FIG. 22 depicts the pharmacokinetic curves of the patients who receivedthe liquid formulation (307, 309 and 310) and all courses (n=6) of thefour patients who received MODRA (307, 308, 309 and 310).

The pharmacokinetic results of the liquid formulation versus MODRA, bothin combination with 100 mg ritonavir, are summarized below:

Liquid Formulation (30 mg Docetaxel)

AUC_(inf) (95% confidence interval of the mean): 1156 (808-1504) ng*h/ml

Inter-individual variability: 85% (n=8)

MODRA (30 mg Docetaxel)

AUC_(inf) (95% confidence interval of the mean): 768 (568-968) ng*h/ml

Inter-individual variability: 29% (n=4)

Intra-individual variability: 33% (n=2)

The average AUC of MODRA was calculated using the 6 curves from fourpatients. The first dose of MODRA administered to each patient, was usedto calculate the inter-individual variability. The intra-individualvariability is based on data from patients 307 and 308 who received twodoses of MODRA.

Conclusions

The tested docetaxel Liquid Formulation results in an AUC value that isapproximately 1.5 fold higher than the same dose (30 mg) given in thenovel capsule formulation (MODRA).

The inter-individual variability of the liquid formulation is high (85%)while the inter-individual variability of the capsule formulation issubstantially lower (29%). This is an important feature of the novelcapsule formulation and provides a much better predictable docetaxelexposure. Also for safety reasons low inter-individual variability isvery much desired in oral chemotherapy regimens.

The intra-individual variability (limited data) is in the same order ofmagnitude as the inter-individual variability.

A second boosting dose of 100 mg ritonavir ingested 4 hours afterdocetaxel administration increases the docetaxel AUC 1.5 fold.

Comparison of Oral Capsule Formulations Compared to i.v. Administration

FIG. 23 shows pharmacokinetic curves after i.v. (20 mg docetaxel as ai.v. 1-hour infusion, Taxotere®) (n=5 patients) and oral administrationof docetaxel (30 mg docetaxel; MODRA capsules, see above) (n=4 patients;6 courses). Both i.v. and oral docetaxel administration was combinedwith administration of 100 mg ritonavir (capsule, Norvir®). According toinstitutional guidelines, for both oral and i.v. docetaxel, all patientswere treated with oral dexamethason. A dose of 4 mg dexamethason wasgiven 1 hour prior to the study drugs, followed by 4 mg every 12 hours(2 times). One hour prior to docetaxel treatment, patients also received1 mg granisetron (Kytril®) to prevent nausea and vomiting.

The bioavailability of the MODRA capsules was calculated by:

(AUC 30  mg  oral/AUC 20  mg  iv) × (20/30) × 100% = 73%(SD 18%).

This shows that the bioavailability of the capsules is relatively highwith a low inter-individual variability.

The foregoing Examples are intended to illustrate specific embodimentsof the present invention and are not intended to limit the scopethereof, the scope being defined by the appended claims. All documentscited herein are incorporated herein by reference in their entirety.

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1. A composition, which is: (a) a solid pharmaceutical compositioncomprising a substantially amorphous taxane, a hydrophilic carrier, anda surfactant; (b) a pharmaceutical composition for oral administration,comprising a substantially amorphous taxane and a carrier wherein thesubstantially amorphous taxane is prepared by lyophilisation; or (c) acomposition comprising a taxane and a CYP3A4 inhibitor together with oneor more pharmaceutically acceptable excipients.
 2. The composition ofclaim 1 which is the solid pharmaceutical composition comprising thesubstantially amorphous taxane, the hydrophilic carrier, and thesurfactant, wherein: (a) the taxane and the carrier are in the form of asolid dispersion; (b) the taxane, the carrier and the surfactant are inthe form of a solid dispersion; (c) the taxane is selected fromdocetaxel, paclitaxel, BMS-275183, functional derivatives thereof andpharmaceutically acceptable salts or esters thereof; (d) the taxane isselected from docetaxel, paclitaxel, functional derivatives thereof andpharmaceutically acceptable salts or esters thereof; (e) the carrier isPVP; (f) the carrier is PVP and the PVP is selected from PVP-K12,PVP-K15, PVP-K17, PVP-K25, PVP-K30, PVP-K60 and PVP-K90; (g) the carrieris PVP and the PVP is selected from PVP-K30, PVP-K60 and PVP-K90; (h)the surfactant is selected from sodium dodecyl sulphate (SDS), sorbitanesters (sorbitan fatty acid esters), polyoxyethylene stearates,polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oilderivatives, polyoxyethylene alkyl ethers, poloxamer, glycerylmonooleate, docusate sodium, cetrimide, benzyl bezoate, benzalkoniumchloride, benzethonium chloride, hypromellose, non-ionic emulsifyingwax, anionic emulsifying wax and triethyl citrate; (i) the surfactant isSDS; (j) the taxane to carrier weight ratio is between about 0.01:99.99w/w and about 75:25 w/w; (k) the taxane to carrier weight ratio isbetween about 0.01:99.99 w/w and about 30:70 w/w; (l) the weight ratioof surfactant, to taxane and carrier combined, is between about 1:99 w/wand about 50:50 w/w; (m) the weight ratio of surfactant, to taxane andcarrier combined, is between about 2:98 w/w and about 17:83 w/w; (n) thesubstantially amorphous taxane is prepared by lyophilisation; or (o) thesubstantially amorphous taxane is prepared by lyophilisation of a taxanesolution in a capsule for oral administration.
 3. The composition ofclaim 1 which is the solid pharmaceutical composition comprising thesubstantially amorphous taxane, the hydrophilic carrier, and thesurfactant, further comprising: (a) one or more additionalpharmaceutically active ingredients; (b) one or more additionalpharmaceutically active ingredients, wherein the one or more additionalpharmaceutically active ingredients comprises a CYP3A4 inhibitor; (c)one or more additional pharmaceutically active ingredients, wherein theone or more additional pharmaceutically active ingredients comprises aCYP3A4 inhibitor, wherein the CYP3A4 inhibitor is ritonavir.
 4. Thecomposition of claim 1 which comprises the taxane and the CYP3A4inhibitor together with one or more pharmaceutically acceptableexcipients, wherein: (a) the CYP3A4 inhibitor is ritonavir; (b) thetaxane is selected from docetaxel, paclitaxel, BMS-275183, functionalderivatives thereof and pharmaceutically acceptable salts or estersthereof; (c) the taxane is docetaxel, a functional derivative thereof ora pharmaceutically acceptable salt or ester thereof; (d) the compositioncomprises between about 0.1 mg and about 1000 mg of the taxane; (e) thecomposition is intended for weekly administration and comprises betweenabout 30 mg and about 500 mg of the taxane; (f) the composition isintended for daily administration and comprises between about 0.1 mg andabout 100 mg of the taxane; (g) which comprises between about 0.1 mg andabout 1200 mg of ritonavir; (h) the composition is intended for weeklyadministration and comprises between about 50 mg and 1200 mg ofritonavir; (i) the composition is intended for daily administration andcomprises between about 50 mg and 1200 mg of ritonavir; or (j) thecomposition is intended for weekly administration and comprises about100 mg of the taxane and about 100 mg of ritonavir.
 5. A method selectedfrom the group consisting of: (a) a method of treating a neoplasticdisease, comprising administering to a subject in need thereof aneffective amount of the composition according to claim 1; (b) a methodof treating a neoplastic disease, comprising administering to a subjectin need thereof an effective amount of a taxane and a CYP3A4 inhibitor;(c) a method of treating a neoplastic disease, comprising administeringa composition comprising a taxane and one or more pharmaceuticallyacceptable excipients to a subject receiving a CYP3A4 inhibitorsimultaneously, separately or sequentially with the taxane; (d) a methodof treating a neoplastic disease, comprising administering a compositioncomprising a CYP3A4 inhibitor and one or more pharmaceuticallyacceptable excipients to a subject receiving a taxane simultaneously,separately, or sequentially with the CYP3A4 inhibitor; and (e) ofpreparing the composition of claim 1, comprising dissolving the taxane,the hydrophilic carrier and the surfactant in a solvent; andlyophilising the solution to form the composition.
 6. The method ofclaim 5, wherein the method is the method of treating a neoplasticdisease, comprising administering to a subject in need thereof aneffective amount of a taxane and a CYP3A4 inhibitor, wherein: (a) theCYP3A4 inhibitor is ritonavir; (b) the taxane is selected fromdocetaxel, paclitaxel, BMS-275183, functional derivatives thereof andpharmaceutically acceptable salts or esters thereof; (c) the taxane isdocetaxel, a functional derivative thereof or a pharmaceuticallyacceptable salt or ester thereof; (d) the taxane is administeredsubstantially simultaneously with the CYP3A4 inhibitor; (e) the CYP3A4inhibitor is administered approximately 60 minutes before the taxane;(f) the taxane is administered at weekly intervals in a dose of betweenabout 30 mg and 500 mg; (g) the taxane is administered at dailyintervals in a dose of between about 0.1 mg and 100 mg; (h) the CYP3A4inhibitor is ritonavir and the ritonavir is administered at weeklyintervals in a dose of between about 50 mg and 1200 mg; (i) the CYP3A4inhibitor is ritonavir and the ritonavir is administered at dailyintervals in a dose of between about 50 mg and 1200 mg; (j) the CYP3A4inhibitor is ritonavir and the taxane and ritonavir are administered atweekly intervals in a dose of about 100 mg of the taxane and about 100mg of ritonavir; (k) the neoplastic disease is a solid tumour; (l) theneoplastic disease is a solid tumour, and the solid tumour is selectedfrom breast, lung, gastric, colorectal, head & neck, oesophagus, liver,renal, pancreatic, bladder, prostate, testicular, cervical, endometrial,ovarian cancer and NHL; (m) the neoplastic disease is a solid tumour,and the solid tumour is selected from breast, ovarian, prostate,gastric, head & neck and non-small cell lung cancer; (n) the subject ishuman; (o) the method further comprises the administration of a boosterdose of CYP3A4 inhibitor a predetermined period of time after theadministration of the first dose of CYP3A4 inhibitor; (p) the methodfurther comprises the administration of a booster dose of CYP3A4inhibitor a predetermined period of time after the administration of thefirst dose of CYP3A4 inhibitor and the booster dose of CYP3A4 inhibitoris ritonavir; or (q) the method further comprises the administration ofa booster dose of CYP3A4 inhibitor a predetermined period of time afterthe administration of the first dose of CYP3A4 inhibitor and the boosterdose of CYP3A4 inhibitor is ritonavir, wherein the booster dose ofritonavir is about 100 mg.
 7. The method of claim 5, wherein the methodis the method of treating a neoplastic disease comprising administeringto a subject in need thereof a composition comprising a taxane and oneor more pharmaceutically acceptable excipients to a subject receiving aCYP3A4 inhibitor simultaneously, separately or sequentially with thetaxane, wherein: (a) the CYP3A4 inhibitor is ritonavir; or (b) thecomposition comprising a taxane is a composition comprising asubstantially amorphous taxane, a hydrophilic carrier, and a surfactant.8. The method of claim 5, which is the method of treating a neoplasticdisease comprising administering a composition comprising a CYP3A4inhibitor and one or more pharmaceutically acceptable excipients, to asubject receiving a taxane simultaneously, separately or sequentiallywith the CYP3A4 inhibitor, wherein: (a) the CYP3A4 inhibitor isritonavir. (b) taxane being received by the subject is in the form of acomposition of claim 1.